Molecules having certain pesticidal utilities, and intermediates, compositions, and processes related thereto

ABSTRACT

This disclosure relates to the field of molecules having pesticidal utility against pests in phyla Nematoda, Arthropoda, and/or Mollusca, processes to produce such molecules and intermediates used in such processes, compositions containing such molecules, and processes of using such molecules against such pests. These molecules may be used, for example, as nematicides, acaricides, insecticides, miticides, and/or molluscicides. This document discloses molecules having the following formula (“Formula One”).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/208,394 filed on Mar. 13, 2014, which claims the benefit and priorityfrom U.S. provisional application Ser. No. 61/784,020 filed on Mar. 13,2013, where the contents of which are incorporated by reference in theirentireties.

This application is also a continuation of U.S. patent application Ser.No. 14/661,389 filed on Mar. 18, 2015, which is a continuation of U.S.patent application Ser. No. 14/208,430 filed on Mar. 13, 2014, now U.S.Pat. No. 9,029,560, which claims the benefit and priority from U.S.provisional application Ser. No. 61/784,020, which was filed on Mar. 14,2013, where entire contents of which are incorporated by reference intheir entireties.

FIELD OF THE DISCLOSURE

This disclosure relates to the field of molecules having pesticidalutility against pests in Phyla Nematoda, Arthropoda, and Mollusca,processes to produce such molecules and intermediates used in suchprocesses, compositions containing such molecules, and processes ofusing such molecules against such pests. These molecules may be used,for example, as nematicides, acaricides, insecticides, miticides, andmolluscicides.

BACKGROUND OF THE DISCLOSURE

“Many of the most dangerous human diseases are transmitted by insectvectors” (Rivero, A. et al., Insect Control of Vector-Borne Diseases:When is Insect Resistance a Problem? Public Library of SciencePathogens, 6(8) (2010)). Historically, vector-borne diseases, such as,malaria, dengue, yellow fever, plague, and louse-borne typhus, amongothers, were responsible for more human disease and death from the1600's through the early 1900's than all other causes combined (GublerD., Resurgent Vector-Borne Diseases as a Global Health Problem, EmergingInfectious Diseases, Vol. 4, No. 3, July-September (1998)). Currently,vector-borne diseases are responsible for about 17% of the globalparasitic and infectious diseases. It has been estimated that about 250million people around the world have malaria and about 800,000 deathsoccur each year—85% of those deaths are children under the age of five.A further 250,000 to 500,000 cases of dengue hemorrhagic fever occureach year (Matthews, G., Integrated Vector Management: controllingvectors of malaria and other insect vector borne diseases (2011)).Vector control plays a critical role in the prevention and control ofinfectious diseases. However, insecticide resistance, includingresistance to multiple insecticides, has arisen in all insect speciesthat are major vectors of human diseases (Rivero, A. et al.).

Each year insects, plant pathogens, and weeds destroy more than 40% ofall potential food production. This loss occurs despite the applicationof pesticides and the use of a wide array of non-chemical controls, suchas crop rotations and biological controls. If just some of this foodcould be saved, it could be used to feed the more than three billionpeople in the world who are malnourished (Pimental, D., Pest Control inWorld Agriculture, Agricultural Sciences—Vol. II (2009)).

Plant parasitic nematodes are among the most widespread pests, and arefrequently one of the most insidious and costly. It has been estimatedthat losses attributable to nematodes are from about 9% in developedcountries to about 15% in undeveloped countries. However, in the UnitedStates of America, a survey of 35 States on various crops indicatednematode-derived losses of up to 25% (Nicol, J. et al., Current NematodeThreats to World Agriculture, Genomic and Molecular Genetics ofPlant—Nematode Interactions (Eds. Jones, J. et al.), Chapter 2, (2011)).

It is noted that gastropods (slugs and snails) are pests of lesseconomic importance than insects or nematodes, but in certain areas,gastropods may reduce yields substantially, severely affecting thequality of harvested products, as well as transmitting human, animal,and plant diseases. While only a few dozen species of gastropods areserious regional pests, a handful of species are important pests on aworld-wide scale. In particular, gastropods affect a wide variety ofagricultural and horticultural crops, such as arable, pastoral, andfiber crops; vegetables; bush and tree fruits; herbs; and ornamentals(Speiser, B., Molluscicides, Encyclopedia of Pest Management (2002)).

Termites cause damage to all kinds of private and public structures, aswell as to agricultural and forestry resources. In 2003, it wasestimated that termites cause over US$20 billion in damage world-wideeach year (Su, N. Y., Overview of the global distribution and control ofthe Formosan subterranean termite, Sociobiology 2003, 41, 177-192).

Therefore, for many reasons, including the above reasons, a need existsfor new pesticides.

DEFINITIONS

The examples given in the definitions are generally non-exhaustive andmust not be construed as limiting the molecules disclosed in thisdocument. It is understood that a substituent should comply withchemical bonding rules and steric compatibility constraints in relationto the particular molecule to which it is attached.

“Alkenyl” means an acyclic, unsaturated (at least one carbon-carbondouble bond), branched or unbranched, substituent consisting of carbonand hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.

“Alkenyloxy” means an alkenyl further consisting of a carbon-oxygensingle bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.

“Alkoxy” means an alkyl further consisting of a carbon-oxygen singlebond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, and tert-butoxy.

“Alkyl” means an acyclic, saturated, branched or unbranched, substituentconsisting of carbon and hydrogen, for example, methyl, ethyl, propyl,isopropyl, butyl, and tert-butyl.

“Alkynyl” means an acyclic, unsaturated (at least one carbon-carbontriple bond), branched or unbranched, substituent consisting of carbonand hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.

“Alkynyloxy” means an alkynyl further consisting of a carbon-oxygensingle bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, andoctynyloxy.

“Aryl” means a cyclic, aromatic substituent consisting of hydrogen andcarbon, for example, phenyl, naphthyl, and biphenyl.

“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at leastone carbon-carbon double bond) substituent consisting of carbon andhydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl,norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl,hexahydronaphthyl, and octahydronaphthyl.

“Cycloalkenyloxy” means a cycloalkenyl further consisting of acarbon-oxygen single bond, for example, cyclobutenyloxy,cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.

“Cycloalkyl” means a monocyclic or polycyclic, saturated substituentconsisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl,cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.

“Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygensingle bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,norbornyloxy, and bicyclo[2.2.2]octyloxy.

“Halo” means fluoro, chloro, bromo, and iodo.

“Haloalkoxy” means an alkoxy further consisting of, from one to themaximum possible number of identical or different, halos, for example,fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy,trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.

“Haloalkyl” means an alkyl further consisting of, from one to themaximum possible number of, identical or different, halos, for example,fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl,trichloromethyl, and 1,1,2,2-tetrafluoroethyl.

“Heterocyclyl” means a cyclic substituent that may be fully saturated,partially unsaturated, or fully unsaturated, where the cyclic structurecontains at least one carbon and at least one heteroatom, where saidheteroatom is nitrogen, sulfur, or oxygen. Examples of aromaticheterocyclyls include, but are not limited to, benzofuranyl,benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl,benzothiazolyl, cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl,and triazolyl. Examples of fully saturated heterocyclyls include, butare not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl,tetrahydrofuranyl, and tetrahydropyranyl. Examples of partiallyunsaturated heterocyclyls include, but are not limited to,1,2,3,4-tetrahydro-quinolinyl, 4,5-dihydro-oxazolyl,4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and2,3-dihydro-[1,3,4]-oxadiazolyl.

DETAILED DESCRIPTION OF THE DISCLOSURE

This document discloses molecules having the following formula (“FormulaOne”)

wherein:(A) Ar¹ is selected from

(1) phenyl, pyridazinyl, pyridyl, pyrimidinyl, or

(2) substituted phenyl, substituted pyridazinyl, substituted pyridyl, orsubstituted pyrimidinyl,

-   -   wherein said substituted phenyl, substituted pyridazinyl,        substituted pyridyl, and substituted pyrimidinyl, have one or        more substituents independently selected from H, F, Cl, Br, I,        CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆        halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆        alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),        C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆        alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl),        phenyl, phenoxy, substituted phenyl and substituted phenoxy    -   wherein such substituted phenyl and substituted phenoxy have one        or more substituents independently selected from H, F, Cl, Br,        I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,        C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆        alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),        C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆        alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl),        phenyl, and phenoxy;        (B) Het is a 5- or 6-membered, saturated or unsaturated,        heterocyclic ring, containing one or more heteroatoms        independently selected from nitrogen, sulfur, or oxygen, and        where Ar¹ and Ar² are not ortho to each other (but may be meta        or para, such as, for a five-membered ring they are 1,3 and for        a 6-membered ring they are either 1,3 or 1,4) and where said        heterocyclic ring may also be substituted with one or more        substituents independently selected from H, F, Cl, Br, I, CN,        NO₂, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆        halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆        alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),        C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆        alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl),        phenyl, phenoxy, substituted phenyl and substituted phenoxy

wherein such substituted phenyl and substituted phenoxy have one or moresubstituents independently selected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), phenyl, and phenoxy;

(C) Ar² is selected from

(1) phenyl, pyridazinyl, pyridyl, pyrimidinyl, or

(2) substituted phenyl, substituted pyridazinyl, substituted pyridyl, orsubstituted pyrimidinyl,

-   -   wherein said substituted phenyl, substituted pyridazinyl,        substituted pyridyl, and substituted pyrimidinyl, have one or        more substituents independently selected from H, F, Cl, Br, I,        CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆        halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆        alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),        C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆        alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl),        phenyl, phenoxy, substituted phenyl and substituted phenoxy    -   wherein such substituted phenyl and substituted phenoxy have one        or more substituents independently selected from H, F, Cl, Br,        I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,        C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR^(x)R^(y), (C₁-C₆        alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₁-C₆ haloalkyl),        C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆        alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆        alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy;        (D) R¹ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl),        C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆        alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl),        (C₁-C₆ alkyl)OC(═O)(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl),        and (C₁-C₆ alkyl)OC(═O)O(C₁-C₆ alkyl),

wherein each alkyl, cycloalkyl, cycloalkoxy, alkoxy, alkenyl, andalkynyl are optionally substituted with one or more substituentsindependently selected from F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl),OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y),C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy;

(E) R² is selected from (J), H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C(═O)(C₁-C₆ alkyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl),(C₁-C₆ alkyl)S(C₁-C₆ alkyl), C₁-C₆ alkylphenyl, C₁-C₆ alkyl-O-phenyl,C(═O)(Het-1), (Het-1), (C₁-C₆ alkyl)-(Het-1), C₁-C₆ alkyl-O—C(═O)C₁-C₆alkyl, C₁-C₆ alkyl-O—C(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl-O—C(═O)OC₁-C₆alkyl, C₁-C₆ alkyl-O—C(═O)NR^(x)R^(y), C₁-C₆ alkyl C(═O)N(R^(x))C₁-C₆alkyl-(Het-1), C₁-C₆ alkylC(═O)(Het-1), C₁-C₆ alkylC(═O)N(R^(x))C₁-C₆alkyl(N(R^(x))(R^(y)))(C(═O)OH), C₁-C₆ alkylC(═O)N(R^(x))C₁-C₆alkylN(R^(x))(R^(y)), C₁-C₆ alkylC(═O)N(R^(x))C₁-C₆alkylN(R^(x))C(═O)—O—C₁-C₆ alkyl, C₁-C₆ alkylC(═O)N(R^(x))C₁-C₆alkyl(N(R^(x))C(═O)—O—C₁-C₆ alkyl)(C(═O)OH), C₁-C₆alkylC(═O)(Het-1)C(═O)—O—C₁-C₆ alkyl, C₁-C₆ alkyl-O—C(═O)—O—C₁-C₆ alkyl,C₁-C₆ alkyl-O—C(═O)C₁-C₆ alkyl, C₁-C₆ alkyl-O—C(═O)C₃-C₆ cycloalkyl,C₁-C₆ alkyl-O—C(═O)(Het-1), C₁-C₆ alkyl-O—C(═O)C₁-C₆alkyl-N(R^(x))C(═O)—O—C₁-C₆ alkyl, C₁-C₆ alkyl-NR^(x)R^(y), (C₁-C₆alkyl)S-(Het-1) or C₁-C₆ alkyl-O-(Het-1),

wherein each alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, and (Het-1)are optionally substituted with one or more substituents independentlyselected from F, Cl, Br, I, CN, NO₂, NR^(x)R^(y), C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl),S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl),C(═O)H, C(═O)OH, C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y), C(═O)(C₁-C₆alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl),C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆alkyl), phenyl, phenoxy, Si(C₁-C₆ alkyl)₃, S(═O)_(n)NR^(x)R^(y), or(Het-1);

(F) R³ is selected from phenyl, C₁-C₆ alkylphenyl, C₁-C₆ alkyl-O-phenyl,C₂-C₆ alkenyl-O-phenyl, (Het-1), C₁-C₆ alkyl(Het-1), or C₁-C₆alkyl-O-(Het-1),

wherein each alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, and (Het-1)are optionally substituted with one or more substituents independentlyselected from F, Cl, Br, I, CN, NO₂, NR^(x)R^(y), C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₃-C₆cycloalkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), O(C₁-C₆ alkyl), S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, and (Het-1);

(G) R⁴ is selected from (J), H, or C₁-C₆ alkyl;

(H) Q¹ is selected from O or S,

(I) R^(x) and R^(y) are independently selected from H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), and phenyl,

wherein each alkyl, cycloalkyl, cycloalkoxy, alkoxy, alkenyl, alkynyl,phenyl, phenoxy, and (Het-1), are optionally substituted with one ormore substituents independently selected from F, Cl, Br, I, CN, NO₂,oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl,S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl),OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)OH, C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, halophenyl,phenoxy, and (Het-1),

or R^(x) and R^(y) together can optionally form a 5- to 7-memberedsaturated or unsaturated cyclic group which may contain one or moreheteroatoms selected from nitrogen, sulfur, and oxygen, and where saidcyclic group may be substituted with F, Cl, Br, I, CN, oxo, thioxo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl,C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl,S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl),OSO₂(C₁-C₆ haloalkyl), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, substitutedphenyl, phenoxy, and (Het-1);

(J) R² and R⁴ may be a 1- to 4-membered saturated or unsaturated,hydrocarbyl link, which may contain one or more heteroatoms selectedfrom nitrogen, sulfur, and oxygen, and together with C^(x)(Q¹)(N^(x))forms a cyclic structure, wherein said hydrocarbyl link may optionallybe substituted with one or more substituents independently selected fromR⁵, R⁶, and R⁷, wherein each R⁵, R⁶, and R⁷ is selected from H, F, Cl,Br, I, CN, OH, C₁-C₆ alkyl, oxo, thioxo, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₃-C₆cycloalkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)(C₁-C₆alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl),C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆alkyl), phenyl, substituted phenyl, phenoxy, or (Het-1);(K) (Het-1) is a 5- or 6-membered, saturated or unsaturated,heterocyclic ring, containing one or more heteroatoms independentlyselected from nitrogen, sulfur or oxygen, wherein said heterocyclic ringmay also be substituted with one or more substituents independentlyselected from H, F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, substituted phenyl andsubstituted phenoxy,

wherein such substituted phenyl and substituted phenoxy have one or moresubstituents independently selected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), phenyl, and phenoxy;

(L) L is linker selected from

(1) a saturated or unsaturated, substituted or unsubstituted, linear(C₁-C₄)hydrocarbyl linker, or

(2) a saturated or unsaturated, substituted or unsubstituted, cyclic(C₃-C₈)hydrocarbyl group linker,

wherein each of said linkers connects Ar² to N^(Y) and

wherein said substituted linear (C₁-C₄)hydrocarbyl linker andsubstituted cyclic (C₃-C₈)hydrocarbyl linker has one or moresubstituents independently selected from R⁸, R⁹, R¹⁰, R¹¹, and R¹²,wherein each R⁸, R⁹, R¹⁰, R¹¹, and R¹², is selected from F, Cl, Br, I,CN, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, C₃-C₆halocycloalkyl, or phenyl; and

(M) n is each individually 0, 1, or 2.

In another embodiment Ar¹ is a substituted phenyl. This embodiment maybe used in combination with the other embodiments of Het, Ar², R¹, R²,R³, R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Ar¹ is a substituted phenyl that has one or moresubstituents selected from C₁-C₆ haloalkyl and C₁-C₆ haloalkoxy. Thisembodiment may be used in combination with the other embodiments of Het,Ar², R¹, R², R³, R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Ar¹ is a substituted phenyl that has one or moresubstituents selected from CF₃, OCF₃, and OC₂F₅. This embodiment may beused in combination with the other embodiments of Het, Ar², R¹, R², R³,R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Het is selected from benzofuranyl,benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl,benzothiazolyl, cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl,triazolyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydro-quinolinyl,4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl,and 2,3-dihydro-[1,3,4]-oxadiazolyl.

In another embodiment Het is triazolyl. This embodiment may be used incombination with the other embodiments of Ar¹, Ar², R¹, R², R³, R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Het is 1,2,4 triazolyl. This embodiment may beused in combination with the other embodiments of Ar¹, Ar², R¹, R², R³,R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Het is oxadiazolyl. This embodiment may be used incombination with the other embodiments of Ar¹, Ar², R¹, R², R³, R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Het is 1,3,4 oxadiazolyl. This embodiment may beused in combination with the other embodiments of Ar¹, Ar², R¹, R², R³,R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Het is pyrazolyl. This embodiment may be used incombination with the other embodiments of Ar¹, Ar², R¹, R², R³, R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Ar² is phenyl. This embodiment may be used incombination with the other embodiments of Ar¹, Het, R¹, R², R³, R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Ar² is a substituted phenyl. This embodiment maybe used in combination with the other embodiments of Ar¹, Het, R¹, R²,R³, R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Ar² is a substituted phenyl that has one or moresubstituents selected from C₁-C₆ alkyl. This embodiment may be used incombination with the other embodiments of Ar¹, Het, R¹, R², R³, R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Ar² is a substituted phenyl that has one or moresubstituents wherein said substituent is CH₃. This embodiment may beused in combination with the other embodiments of Ar¹, Het, R¹, R², R³,R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R¹ is H. This embodiment may be used incombination with the other embodiments of Ar¹, Het, Ar², R², R³, R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R² is (J), H, C₁-C₆ alkyl, C₁-C₆alkyl-O—C(═O)C₁-C₆ alkyl, C₁-C₆ alkyl-O—C(═O)N(R^(x)R^(y)), or (C₁-C₆alkyl)S-(Het-1). This embodiment may be used in combination with theother embodiments of Ar¹, Het, Ar², R¹, R³, R⁴, Q¹, R² and R⁴hydrocarbyl links, and/or L.

In another embodiment R² is (J), H, CH₃, C₁-C₆ alkyl, CH₂OC(═O)CH(CH₃)₂,CH₂OC(═O)N(H)(C(═O)OCH₂Ph), or CH₂S(3,4,5-trimethoxy-2-tetrahydropyran).This embodiment may be used in combination with the other embodiments ofAr¹, Het, Ar², R¹, R³, R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R³ is substituted phenyl. This embodiment may beused in combination with the other embodiments of Ar¹, Het, Ar², R¹, R²,R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R³ is substituted phenyl wherein said substitutedphenyl has one or more substituents selected from F, Cl, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, and phenyl. This embodiment may be usedin combination with the other embodiments of Ar¹, Het, Ar², R¹, R², R⁴,Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R³ is substituted phenyl wherein said substitutedphenyl has one or more substituents selected from F, CH₃, 2-CH(CH₃)₂,CH(CH₃)(C₂H₅), OCH₃, and phenyl. This embodiment may be used incombination with the other embodiments of Ar¹, Het, Ar², R¹, R², R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R³ is substituted phenyl wherein said substitutedphenyl has more than one substituent and at least one pair of saidsubstituents are not ortho to each other. This embodiment may be used incombination with the other embodiments of Ar¹, Het, Ar², R¹, R², R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R³ is C₁-C₆ alkylphenyl. This embodiment may beused in combination with the other embodiments of Ar¹, Het, Ar², R¹, R²,R⁴, Q¹, R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R³ is (Het-1). This embodiment may be used incombination with the other embodiments of Ar¹, Het, Ar², R¹, R², R⁴, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R⁴ is H. This embodiment may be used incombination with the other embodiments of Ar¹, Het, Ar², R¹, R², R³, Q¹,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment Q¹ is O. This embodiment may be used incombination with the other embodiments of Ar¹, Het, Ar², R¹, R², R³, R⁴,R² and R⁴ hydrocarbyl links, and/or L.

In another embodiment R² and R⁴ is a hydrocarbyl link wherein saidhydrocarbyl link is substituted with oxo or C₁-C₆ alkyl. This embodimentmay be used in combination with the other embodiments of Ar¹, Het, Ar²,R¹, R², R³, R⁴, Q¹, and/or L.

In another embodiment R² and R⁴ is a hydrocarbyl link wherein saidhydrocarbyl link is CH₂C(═O), C(C(OH)(CH₃)₂)C(═O), C(cyclopropyl)C(═O),C(CH₃)₂C(═O), CFHC(═O), CBrHC(═O), CH(CH₃)C(═O), CH₂CH₂, CH₂C(OH)(CH₃),CH₂CH₂CH₂, CH₂CH₂C(═O), CH₂CH(CH₃)CH₂, N(CH₃)C(═O), N(CH₂CH₃)C(═O),CH═C(CH₃), or CH₂CH(CH₃). This embodiment may be used in combinationwith the other embodiments of Ar¹, Het, Ar², R¹, R², R³, R⁴, Q¹, and/orL.

In another embodiment L is CH₂, CH₂CH₂, CH₂CH(CH₃), CH₂C(CH₃)₂,CH₂CH(CH₂CH₃), CH═CH, CH(CH₃)CH₂, C(CH₃)₂CH₂, CHBrCH₂,CH₂C(cyclopropyl), CH(CH₂CH₃)CH₂, C(CH₃)═CH, CH₂CH₂CH₂, CH(CH₃)CH(CH₃),CH₂CH₂CH₂CH₂, C≡CCH₂CH₂, cyclopropyl, or cyclohexyl. This embodiment maybe used in combination with the other embodiments of Ar¹, Het, Ar², R¹,R², R³, R⁴, Q¹ and/or R² and R⁴ hydrocarbyl links.

Many of the molecules of Formula One may be depicted in two or moretautomeric forms such as when R¹, R², or R⁴, is H (see for example,“Scheme TAU” below). For the sake of simplifying the schemes, allmolecules have been depicted as existing as a single tautomer. Any andall alternative tautomers are included within the scope of this FormulaOne, and no inference should be made as to whether the molecule existsas the tautomeric form in which it is drawn.

The molecules of Formula One will generally have a molecular mass ofabout 400 Daltons to about 1200 Daltons. However, it is generallypreferred if the molecular mass is from about 300 Daltons to about 1000Daltons, and it is even more generally preferred if the molecular massis from about 400 Daltons to about 750 Daltons.

Preparation of Thiobiurets

Thiobiurets disclosed herein are prepared from the correspondingisocyanate, Ar¹-Het-Ar²-L-NCO (1-2). Usually, these isocyanates are notisolated, but are instead generated in situ from a suitable precursorand used directly in the preparation of a thiobiuret. One such suitableprecursor is an amine (1-1) which can be converted into an isocyanate byusing one of several common reagents such as phosgene, diphosgene,triphosgene, or carbonyldiimidazole (Scheme 1, step a), in a mixedsolvent system such as dichloromethane and water or diethyl ether andwater, in the presence of a base such as sodium bicarbonate ortriethylamine, at temperatures from about −10° C. to about 50° C.

Alternatively, the isocyanates may be generated via a Curtiusrearrangement of an acyl azide, Ar¹-Het-Ar²-L-C(O)N₃ (1-4), which is, inturn, prepared from the corresponding carboxylic acid precursor,Ar¹-Het-Ar²-L-CO₂H (1-3). Formation of an acyl azide (Scheme 1, step b)occurs either by treatment of the acid with ethyl chloroformate andsodium azide in the presence of an amine base such as triethylamine, orwith diphenylphosphoryl azide in the presence of an amine base such astriethylamine. The acyl azide is then made to undergo a Curtiusrearrangement (which may need to be thermally induced), leading to thecorresponding isocyanate (1-3). Depending on the nature of theparticular acyl azide, this rearrangement may occur spontaneously atambient temperature, or it may require heating from about 40° C. toabout 100° C. in a suitable solvent, such as toluene, or acetonitrile,or an ethereal solvent such as dioxane or tetrahydrofuran. Azides ofarylacetic acids are known, though frequently, due to their reactivity,they are not isolated as pure solids. Accordingly, the acyl azideintermediate is not always fully characterized, but may simply be heateddirectly without characterization, to generate the isocyanate.

An isocyanate, Ar¹-Het-Ar²-L-NCO (1-2), can be treated directly with anN-aryl thiourea (2-1) in the presence of about 0.1 to about 2equivalents of an inorganic base such as cesium carbonate or sodiumhydride, resulting in the formation of a thiobiuret (2-2, Scheme 2). Thereaction can be performed at temperatures from about 0° C. to about 100°C., preferably from about 20° C. to about 80° C., in an aprotic solventor solvent mixture chosen from acetonitrile, acetone, toluene,tetrahydrofuran, 1,2-dichloroethane, dichloromethane, or mixturesthereof, but use of acetonitrile is preferred.

Thiobiurets (2-2) generated in situ can be converted directly withoutpurification into a variety of cyclized analogs (Scheme 3), or they canbe isolated from the reaction medium prior to cyclization. Cyclizationcan be achieved by treatment with an α-halo ester such as methylbromoacetate to form 2-imino 1,3-thiazolin-4-ones (3-1, step a)unsubstituted or mono- or di-substituted with R⁵; vicinal dihalides suchas 1-bromo-2-chloroethane or 1,2-dichloroethane, to form2-imino-1,3-thiazolines (3-2, step b) unsubstituted or mono-substitutedwith R⁵ or R⁶; α-halo ketones such as chloroacetone to form2-imino-1,3-thiazoles (3-3, step c) unsubstituted with R⁵ or R⁶; or1,3-dihalopropanes such as 1-bromo-3-chloro-propane to form2-imino-1,3-thiazinanes (3-4, step d) unsubstituted or mono-substitutedwith R⁵ or R⁶ or unsubstituted or mono- or di-substituted with R⁷. Withstep a, use of sodium acetate in a protic solvent such as ethanol ormethanol, at temperatures ranging from about 20° C. to about 70° C. ispreferred. With step b, use of an inorganic base such as potassiumcarbonate in a solvent such as acetonitrile or (preferably) 2-butanone,at a temperature between about 0° C. and about 80° C., is preferred.

An alternative method for preparing analogs having the general structure3-1′ (Scheme 3) is described in Scheme 3a, Intermediate2-iminolthiazolidin-4-one (3-1a, step a) is reacted directly with anisocyanate (1-2), in the presence of about 0.1 to about 2 equivalents ofan inorganic base such as cesium carbonate or sodium hydride to formcyclized thiobiuret (3-1′). The reaction can be performed attemperatures from about 0° C. to about 100° C., preferably from about20° C. to about 80° C., in an aprotic solvent or solvent mixture chosenfrom acetonitrile, acetone, toluene, tetrahydrofuran,1,2-dichloroethane, dichloromethane, or mixtures thereof, but use ofacetonitrile is preferred.

Alternatively, the 2-iminothiazolidin-2-one (3-1a) may be reacted with4-nitrophenyl chloroformate (step b), forming a 4-nitrophenyl carbamateintermediate (3-2a). This reaction is conducted with equimolarquantities of the imine and the chloroformate, in a polar aproticsolvent such as tetrahydrofuran or dioxane, and in the presence of fromabout 0.1 to about 2 equivalents of an inorganic base such as cesiumcarbonate or potassium carbonate, preferably at room temperature. Theintermediate (3-2a) may be isolated by filtration from inorganic saltsand evaporation of solvent, or it can be used directly in step c. Instep c, treatment of 3-2a with a primary alkyl amine Ar₁-Het-Ar₂-L-NHR¹,wherein R¹ is H or alkyl, may generate cyclized thiobiuret (3-1′). Stepc may also be conducted in the presence of an inorganic base such ascesium carbonate or potassium carbonate, from about 0.1 to about 2equivalents, preferably about 1 to about 1.2 equivalents; it is alsomost conveniently run at room temperature, although it may be run attemperatures from about 0° C. to about 100° C.

Thiobiurets (2-2) can also be converted into novel S-alkylated analogsas described in Scheme 3b. For example, reaction of a thiobiuret 2-2with an alkyl iodide (step a), in a protic solvent such as ethanol, andin the presence of a base such as sodium acetate, at temperatures fromabout 0° C. to about 60° C., results in formation of an S—R² substitutedproduct (3-1b). A variation of the reaction conditions described inScheme 3, step c, employs careful control of reaction conditions toensure that the temperature does not exceed 20° C. Under theseconditions, 4-hydroxy-2-iminothiazolidines (3-2b, step b) may beisolated.

Analogs of Formula 1 wherein R² and R⁴ are cyclized to form a2-(R⁵)-4-(R³)-5-imino-1,2,4-thiadiazolidin-3-one (3-4c) may beconstructed as described in Scheme 3c. Following the work described byKaugers, et al (J. Org. Chem 1992, 57, 1671), an N-arylamino1,2,3,4-thiatriazole (3-1c), prepared in one step from the correspondingN³-aryl thiosemicarbazone by oxidation with sodium nitrite, is treatedwith an alkyl isocyanate to form 3-2c. Treatment of 3-2c with a basesuch as sodium methoxide in methanol at room temperature (step b)results in cleavage of the urea bond and formation of a2-(R⁵)-4-(R³)-5-imino-1,2,4-thiadiazolidin-3-one (3-3c). This imine maythen be treated with an isocyanate under conditions equivalent to thosedescribed in Scheme 3a, step a, to form 3-4c.

Preparation of Triaryl-Intermediates

Molecules of Formula One can be prepared by making a triarylintermediate, Ar¹-Het-Ar², and then linking it to an appropriateintermediate to form a desired compound. A wide variety of triarylintermediates can be used to prepare molecules of Formula One, providedthat such triaryl intermediates contain a suitable functional group onAr² to which the rest of the desired functional group can be attached.Suitable functional groups include an amino, isocyanate, carboxyl, or ahalogen (preferably bromo or iodo). These triaryl intermediates can beprepared by methods previously described in the chemical literature,including Crouse, et al., WO2009102736 (the entire disclosure of whichis hereby incorporated by reference).

The triaryl aldehydes used as precursors in preparation of the moleculesof Formula One can be prepared according to procedures described inCrouse, et al., US 2012/0202688 A1. Some of the procedures describedabove require use of halo-aryl intermediates, Ar¹-Het-Ph-Br, which arenovel intermediates. These may be prepared as described in Scheme 4.3-(4-Bromophenyl)-1,2,4-triazole (4-2, step a) is prepared in two stepsfrom 4-bromobenzamide (4-1) under conditions described previously(Crouse, et al., WO2009102736). This triazole can then be coupled to anaryl halide (R═C₁-C₆ haloalkoxy) such as 4-trifluoromethoxyphenylbromobenzene, in the presence of cesium carbonate or potassiumphosphate, in a polar aprotic solvent such as dimethylformamide. Thisreaction is catalyzed by a copper salt such as copper(I) iodide and achelator such as 8-hydroxyquinoline, both present in about 0.05 to about0.25 equivalents, at a temperature ranging between about 80° C. andabout 140° C., to form the 1-aryl-3-(4-bromophenyl)triazole (4-4, stepb).

Preparation of 1-Atom Linked Intermediates

Molecules of Formula One wherein L is a one-carbon linker, can beprepared from acid or amine intermediates described in Scheme 5 andScheme 6, respectively. Acid precursors Ar¹-Het-Ar²-L-CO₂H,unsubstituted or mono- or di-substituted with R⁸; can be prepared asshown in the Scheme 5. Boronic esters (5-2, step a) can be preparedusing Miyaura conditions from halophenyl esters (5-1). Coupling of theboronate esters with a bromo-heterocycle (5-3, step b) can beaccomplished using a palladium catalyst and phosphine ligand, in thepresence of a base, such as sodium bicarbonate, potassium phosphate, orcesium fluoride, in a suitable solvent system, such as dioxane/water, attemperatures from about 50° C. to about 120° C. to form triaryl esterintermediates (5-4, step c). Among palladium catalysts,tetrakis(triphenylphosphine)palladium(0) is preferred, although otherwell-known palladium catalysts may be used. Saponification of the estermay be achieved by using a strong base such as sodium hydroxide orlithium hydroxide in methanol or ethanol with or withouttetrahydrofuran/water to furnish the desired carboxylic acid (5-5, stepc).

Amine precursors Ar¹-Het-Ar²-L-NH₂, unsubstituted or mono- ordi-substituted with R⁸, can be prepared as shown in the Scheme 6.Halobenzyl amines (6-1) may be protected using benzyl chloroformate inthe presence of a base such as triethylamine in an aprotic solvent suchas dichloromethane at about −10° C. to about 10° C. to provideN-carboxybenzyl (Cbz) protected benzyl amines (6-2, step a).Alternatively, other N-protecting groups such as tert-butoxycarbonyl(BOC) or 9-fluorenylmethylcarbonyl (Fmoc) may be employed in step ausing similar conditions described above for Cbz. The Cbz protectedboronic ester 6-3 can be prepared using Miyaura conditions (step b).Coupling of the boronate esters with a bromo-heterocycle (5-3) can beaccomplished using a palladium catalyst and phosphine ligand, in thepresence of a base, such as sodium bicarbonate, potassium phosphate, orcesium fluoride, in a suitable solvent system, such as dioxane/water, attemperatures from about 50° C. to about 120° C. to form N-protectedaminoalkylphenyl intermediates (6-4, step c). Deprotection of the Cbzgroup can be accomplished under acidic conditions with a strong acidsuch as hydrogen bromide, followed by free basing with a base such assodium bicarbonate or sodium hydroxide, to furnish the free amineprecursors Ar¹-Het-Ar²-L-NH₂ (6-5, step d). Similar methods could beapplied to compounds wherein L is greater than 1-carbon.

Preparation of Ethyl Linked Intermediates

Preparation of compounds wherein L is a two-atom group is described inSchemes 7 to Schemes 9. Condensation of the aldehyde (7-1, R⁹═H)(described in US 2012/0202688 A1) with reagents such as ethyldiethylphosphonoacetate or a Wittig reagent such as ethyl2-(triphenylphosphoranylidene)propanoate) or α-substituted acetates suchas ethyl 2-fluoroacetate or ethyl 2-cyanoacetate in the presence of asuitable base such as sodium hydride or n-butyl lithium in aproticsolvents such as tetrahydrofuran or diethyl ether at temperatures fromabout −78° C. to about 20° C. can be used to prepare acrylic esters(7-2, step a) unsubstituted or mono-substituted with R⁹ and R¹⁰.Saponification of the resultant ester may be achieved by using a strongbase such as sodium hydroxide in methanol or ethanol with or withouttetrahydrofuran/water to furnish the vinyl carboxylic acid (7-3, stepb). In some cases the partial condensation of aldehyde (7-1, R⁹═H) mayresult in the isolation of the alcohol intermediate (7-4, step c)especially when R¹⁰ is electron withdrawing. Substitution of thisalcohol with nucleophilic reagents such as Deoxo-Fluor® (step d)followed by saponification as described above (step e) can generatehighly substituted ethyl carboxylic acids (7-5) additionally substitutedwith R¹¹, wherein R¹ is defined as R⁸ above. When the saturated linkageis preferred, the acrylate ester (7-2) can be converted to thecorresponding cyclopropane (7-6, step f) unsubstituted or mono- ordi-substituted with R¹²; with sulfur ylides such as those formed in situfrom trimethyl sulfonium iodide in the presence of an inorganic basesuch as sodium hydride in a polar aprotic solvent such as dimethylsulfoxide or tetrahydrofuran. Likewise the acrylate ester (7-2) can bereduced to the parent alkane (7-8, step h) using hydrogen gas and apalladium catalyst. Both the cyclopropane and the alkane can behydrolyzed under basic conditions described above to generate the freecarboxylic acids 7-7 (step g) and 7-9 (step i), respectively.

In a similar manner, condensation of the ketone (7-1, R⁹=Alkyl)(described in WO 2011017504 A1) with either ethyldiethylphosphonoacetate or a Wittig reagent such as ethyl2-(triphenylphosphoranylidene)propanoate or α-substituted alkyl esterssuch as ethyl 2-fluoroacetate or ethyl 2-cyanoacetate under similarconditions described above may generate the α-alkyl acrylate esters 7-2or alcohols 7-4. Subsequent treatment of 7-2 or 7-4 as described abovefor R⁹═H may lead to either the corresponding unsaturated (7-3) orsaturated (7-5, 7-7, 7-9) carboxylic acids.

Alternatively, compounds wherein L is a 2-carbon linker may also beprepared as shown in Scheme 8. Using conditions first described byMolander et al. Org. Lett., 2007, 9 (2), pp 203-206, coupling of abromide Ar¹-Het-Ar²—Br (8-1, step a), with potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate in the presence ofa palladium catalyst such as palladium(II)acetate, and a base such ascesium carbonate, at temperatures from about 80° C. to about 120° C.,results in the formation of the corresponding2-(tert-butoxycarbonyl)amino)ethyl derivative 8-2. Further treatment ofthis material with from about 1 to about 5 equivalents of an acid suchas trifluoroacetic acid or hydrogen chloride, in an aprotic solvent suchas dichloromethane or dioxane at temperatures from about 0° C. to about50° C., results in the cleavage of the tert-butoxycarbonyl group andformation of the trifluoroacetic acid salt of the amineAr¹-Het-Ar²-L-NH₂ (8-3, step b).

Aminoalkyl precursors Ar¹-Het-Ar²-L-NH₂, wherein L is 2-carbon atoms,mono- or di-substituted with R⁹, wherein R⁹ is defined as above; andunsubstituted or mono-substituted with R¹⁰, wherein R¹⁰ is defined asabove, can be prepared as shown in Scheme 9. Halophenyl carbinols 9-1,wherein X can be selected from Cl, Br, or I, unsubstituted at R⁹ and R¹⁰are available commercially. Carbinols 9-1 that are mono- ordi-substituted at R⁹ can be prepared from the corresponding halophenylacetate (9-I, step a) in similar fashion to that described by Shin etal. Bioorg. Med. Chem. Lett., 2008, 18, pp 4424-4427 followed byreduction with a metal hydride such as lithium aluminum hydride in anethereal solvent such as tetrahydrofuran or diethyl ether attemperatures at or below about 0° C. Both 9-I and 9-II may be furthermono-substituted (step b or step c) with R¹⁰ via reduction to thecorresponding aldehyde with a metal hydride such as diisobutylaluminumhydride and further treatment with a Grignard reagent in a similarfashion to that described by Brimble et al. Org. Lett., 2012, 14 (23),pp 5820-5823. Carbinols 9-1 can be treated with phthalimide underMitsunobu conditions to generate N-phthalimido intermediates 9-2 (stepd). The halide can be converted into a boronic ester under Miyauraconditions to form boronate esters (9-3, step e). Coupling of theboronate esters with a bromo-heterocycle can be accomplished using apalladium catalyst, such tetrakis(triphenylphosphine)palladium(0), inthe presence of a base, such as sodium bicarbonate, in a suitablesolvent system, such as dioxane/water, at temperatures from about 50° C.to about 120° C. to provide N-phthalimido intermediates 9-4 (step f).Deprotection using hydrazine and methanol or other suitable solvent canfurnish the amine 9-5 (step g).

Alternatively, compounds wherein L is a 2-atom linker may also beprepared as shown in Scheme 9a. Olefination of aldehyde (7-1, R⁹═H, stepa) may be achieved with methylenetriphenylphosphorane which can beprepared from methyl triphenylphosphonium iodide in the presence of abase such as sodium hydride or 1,8-diazabicycloundec-7-ene in an aproticsolvent such as tetrahydrofuran or dichloromethane at temperatures ofabout −78° C. to about 40° C. Further treatment of this material (9-2a)with a hydroborating reagent such as 9-borabicyclo(3.3.1)nonane in anaprotic solvent such as tetrahydrofuran followed by oxidation with anoxidant such as hydrogen peroxide can generate ethyl alcohol 9-3a (stepb). Carbinols 9-3a can be treated with phthalimide under Mitsunobuconditions to generate N-phthalimido intermediates 9-5a (step c),wherein R¹⁰═H. Deprotection using hydrazine and methanol or othersuitable solvent can furnish the amine 9-6a (step f). Additionally, 9-3amay be further mono-substituted (step d) with R¹⁰, wherein R¹⁰ isdefined as above, via oxidation to the corresponding aldehyde underSwern conditions followed by addition of a Grignard reagent such asdescribed above (Scheme 9). Carbinols 9-4a can be further treated withphthalimide under Mitsunobu conditions to generate N-phthalimidointermediates 9-5a (step e). Deprotection using hydrazine and methanolor other suitable solvent can furnish the amine 9-6a (step f).

Scheme 9b outlines an alternative route for constructing analogs whereinthe linker L is a two-atom linker. Copper-catalyzed arylation of2,4-pantane-2,4-dione with 8-1 (JACS, 2010, 132, 8273) may provide thesubstituted acetone intermediate 9-1b (step a). Reductive amination(step b), using any of a variety of conditions familiar to those skilledin the art, may generate amine 9-2b, which may be converted into thetarget molecules using conditions described previously in Scheme 2. Whena linker contains a chiral center, such as with intermediate 9-2b, theseintermediates may be separated into their pure isomeric forms either bymeans of a chiral column, or by fractional crystallization of the saltprepared from a chiral acid such as (+) and (−) tartaric acid.

Construction of analogs wherein the ethyl linking group is part of a6-membered ring is may also be accomplished starting from bromide 8-1.Coupling of 8-1 with2-cyclohex-1-enyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Scheme 9b,step c) under standard Suzuki coupling conditions can lead to alkene9-3b. Epoxidation with standard reagents, such asmeta-chloroperoxybenzoic acid (step d), followed by acid-catalyzedrearrangement using indium trichloride (J. Org. Chem. 1998, 63(23),8212) may generates ketone 9-5b. Reductive amination and conversion intothe target molecules can be accomplished using conditions describedabove.

Preparation of Propyl Linked Intermediates

Preparation of compounds wherein L is a three-atom group is described inSchemes 10 and 11. Aminoalkyl precursors Ar¹-Het-Ar²-L-NH₂, wherein L is3-carbon atoms, mono- or di-substituted with R⁹, wherein R⁹ is definedas above; and unsubstituted or mono-substituted with R¹⁰, wherein R¹⁰ isdefined as above; can be prepared as shown in Scheme 10. Halophenylcarbinol 10-1, wherein X is Br and R⁹ and R¹⁰ are H, is availablecommercially. Carbinols 10-1 that are mono- or di-substituted at R⁹ canbe prepared from the corresponding halophenyl acetate (10-I, step a) insimilar fashion to that described by Shin et al. Bioorg. Med. Chem.Lett., 2008, 18, pp 4424-4427, followed by reduction with a metalhydride such as lithium aluminum hydride in an ethereal solvent such astetrahydrofuran at temperatures at or below about 0° C. Both 10-I and10-II may be further mono-substituted (step b or step c) with R¹⁰ viareduction to the corresponding aldehyde with a metal hydride such asdiisobutylaluminum hydride and further treatment with a Grignard reagentsuch as methylmagnesium bromide in a similar fashion to that describedby Brimble et al. Org. Lett., 2012, 14 (23), pp 5820-5823; Carbinols10-1 can be treated with phthalimide under Mitsunobu conditions togenerate N-phthalimido intermediates 10-2 (step d).

The halide can be converted into boronic ester under Miyaura conditionsto form boronate esters (10-3, step e). Coupling of the boronate esterswith a bromo-heterocycle can be accomplished using a palladium catalyst,such tetrakis(triphenylphosphine)palladium(0), in the presence of abase, such as sodium bicarbonate, in a suitable solvent system, such asdioxane/water, at temperatures from about 50° C. to about 120° C. toprovide N-phthalimido intermediates 10-4 (step f). Deprotection usinghydrazine and methanol or other suitable solvent can furnish the amine10-5 (step g).

Alternatively, compounds wherein L is a 3-atom linker may also beprepared as shown in Scheme 11. Bromide Ar¹-Het-Ar²—Br (8-1) can becoupled with an appropriate alkynyl alcohol (11-1, step a) unsubstitutedor mono-substituted with R¹⁰, wherein R¹⁰ is defined as above; in thepresence of a palladium catalyst such as bistriphenylphosphinedichloropalladium(II), copper(I) iodide, and a base such astriethylamine, at temperatures from about 50° C. to about 120° C., togenerate the corresponding alkynyl alcohol derivatives 11-2. Theresultant carbinols 11-2 can be treated with phthalimide under Mitsunobuconditions to generate N-phthalimido intermediates 11-3 (step b) whichcan be converted to amine (11-7, step e) using hydrazine and methanol orother suitable solvent. Carbinols 11-2 can be reduced using a transitionmetal catalyst, such as palladium under an atmosphere of hydrogen toprovide alkenyl or fully saturated alkyl carbinols 11-4 unsubstituted atR¹⁰. Additionally, carbinols 11-2 can be treated with a metal hydridesuch as lithium aluminum hydride to provide the (E)-alkenyl carbinol11-4. Likewise, carbinol 11-2 may be protected with a protecting groupsuch as tert-butyl diphenyl silane, and treated with a hydrometallationreagent such as Schwartz' reagent followed by an electrophile quench,with, for example, elemental iodine or NBS. Alternatively, the carbinol11-2 may be treated with a transmetallation reagent such as pinacoldiboron for further use in transition metal-catalyzed couplingreactions, such as Suzuki or Negishi, to prepare carbinols 11-4 mono- ordi-substituted with R⁹, wherein R⁹ is defined as above (step c).Following deprotection, the resultant carbinols 11-4 can be treated withphthalimide under Mitsunobu conditions to generate N-phthalimidointermediates 11-5 (step d) which can be converted to an amine (11-6,step e) using hydrazine and methanol or other suitable solvent.

Preparation of Butyl Linked Intermediates

Compounds wherein L is a 4-atom linker may be prepared as shown inScheme 12. Bromide Ar¹-Het-Ar²—Br (8-1) can be coupled with anappropriate alkynyl alcohol (12-1, step a) unsubstituted ormono-substituted with R¹⁰, wherein R¹⁰ is defined as above; mono- ordi-substituted with R⁹, wherein R⁹ is defined as above; in the presenceof a palladium catalyst such as bistriphenylphosphine dichloropalladium,copper(I) iodide, and a base such as triethylamine, at temperatures fromabout 50° C. to about 120° C., to generate the corresponding alkynylalcohol derivatives 12-2. The resultant carbinols 12-2 can be treatedwith phthalimide under Mitsunobu conditions (step b) to generateN-phthalimido intermediates 12-3 which can be converted to an amine(12-7, step e) using hydrazine and methanol or other suitable solvents.Carbinols 12-2 can be reduced using a transition metal catalyst, such aspalladium under an atmosphere of hydrogen to provide alkenyl or fullysaturated alkyl carbinols 12-4 (step c) unsubstituted at R¹³.Additionally, carbinols 12-2 can be treated with a metal hydride such aslithium aluminum hydride to provide the (E)-alkenyl carbinols 12-4 (stepc). Likewise, carbinol 12-2 may be protected with a protecting groupsuch as tert-butyl diphenyl silane, and treated with a hydrometallationreagent such as Schwartz' reagent followed by an electrophile quench,with, for example, elemental iodine or NBS. Alternatively the carbinol12-2 may be treated with a transmetallation reagent such as pinacoldiboron for further use in transition metal-catalyzed couplingreactions, such as Suzuki or Negishi, to prepare carbinols 12-4 mono- ordi-substituted with R¹³, wherein R¹³ is defined as R⁸ above (step c).

Following deprotection, the resultant carbinols 12-4 can be treated withphthalimide under Mitsunobu conditions (step d) to generateN-phthalimido intermediates 12-5 which can be converted to an amine(12-6, step e) using hydrazine and methanol or other suitable solvent.Preparation of Substituted Thiobiurets

2-Imino 1,3-thiazolin-4-ones (3-1) may be further functionalized using avariety of conditions. When treated with Selectfluor® and 9-fluorenonein anhydrous acetonitrile (JACS. 2013, 135, 17494.), molecules havingthe formula 3-1 may be converted into the mono-fluoro analogs (13-1).

Treatment with molecular bromine in a non-protic solvent such asdichloromethane at from about 0° C. to about 30° C. (step b) may resultin mono-bromination on the thiazolinone ring (13-2). Alkylation (stepc), using at least 2 equivalents of an alkylating agent R⁵-I and astrong base such as sodium hydride or lithium diisopropylamide in apolar aprotic solvent such as dimethylformamide or tetrahydrofuran maylead to a di-alkylated product (13-3). Treatment with a ketone or analdehyde and an inorganic base such as potassium carbonate or cesiumcarbonate may result in the formation of a carbinol (13-4). For analogsof compounds of the formula 3-1 wherein L is a —CH₂CH₂— group,free-radical bromination using N-bromosuccinimide and a free radicalinitiator such as azobis (isobutyronitrile) in carbon tetrachloride atabout 30° C. to about 77° C. may lead to the mono-brominated product(13-5) wherein the bromine is incorporated into the ethyl linker.

EXAMPLES

These examples are for illustration purposes and are not to be construedas limiting the disclosure to only the embodiments disclosed in theseexamples.

Starting materials, reagents, and solvents that were obtained fromcommercial sources were used without further purification. Anhydroussolvents were purchased as Sure/Seal™ from Aldrich and were used asreceived. Melting points were obtained on a Thomas Hoover Unimeltcapillary melting point apparatus or an OptiMelt Automated Melting PointSystem from Stanford Research Systems and are uncorrected. Examplesusing “room temperature” were conducted in climate controlledlaboratories with temperatures ranging from about 20° C. to about 24° C.Molecules are given their known names, named according to namingprograms within ISIS Draw, ChemDraw or ACD Name Pro. If such programsare unable to name a molecule, the molecule is named using conventionalnaming rules. ¹H NMR spectral data are in ppm (δ) and were recorded at300, 400 or 600 MHz, and ¹³C NMR spectral data are in ppm (δ) and wererecorded at 75, 100 or 150 MHz, unless otherwise stated.

Example 1: Preparation of3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1)

To a 100 mL round bottomed flask, equipped with a stir bar, was addedcopper(I) iodide (0.397 g, 2.08 mmol), 3-bromo-1H-1,2,4-triazole (4.62g, 31.2 mmol), and cesium carbonate (6.79 g, 20.83 mmol), as solids.These solids were diluted with anhydrous dimethyl sulfoxide (34.7 mL).Then 1-iodo-4-(trifluoromethoxy)benzene (1.65 mL, 10.4 mmol) was addedas a liquid. The flask was placed under nitrogen atmosphere, and thesuspension was heated to an internal temperature of 100° C. for 20hours. The reaction mixture was allowed to cool to room temperature andfiltered through a pad of Celite®, washing with excess ethyl acetate(200 mL). The filtrate was poured into a brine solution (200 mL), andthe layers were partitioned. The aqueous phase was extracted withadditional ethyl acetate (2×100 mL). The combined organic layers weredried over anhydrous magnesium sulfate, filtered, and concentrated. Theresulting residue was purified via flash column chromatography using10-50% ethyl acetate/hexanes as eluent to afford the title compound as awhite solid (1.80 g, 54%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H),7.97 (d, J=8.9 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −57.06; ESIMS m/z 308, 310 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 1.

Preparation of 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole(C1a)

The title compound was prepared as described in Example 1 using1-iodo-4-pentafluoroethoxybenzene and isolated as a white solid (1.60 g,31%): mp 72-74° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 7.75-7.68(m, 2H), 7.42-7.36 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.94, −87.92;ESIMS m/z 357, 359 ([M+H]⁺).

Preparation of 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole(C1b)

The title compound was prepared as described in Example 1 using1-iodo-4-trifluoromethylbenzene and isolated as a white solid (2.32 g,31%): mp 104-105° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.81 (s,4H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.64; ESIMS m/z 292, 294 ([M+H]⁺).

Example 2: Preparation of methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2)

To a 200 mL round bottomed flask, equipped with a stir bar, was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.799 g,1.09 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(6.65 g, 26.2 mmol), and potassium acetate (4.28 g, 43.7 mmol) assolids. These solids were diluted with dioxane (100 mL). The flask wassealed and pumped and purged with nitrogen atmosphere. Then methyl2-(4-bromophenyl)acetate (5.00 g, 21.8 mmol) was added. The reactionmixture was then warmed to an internal temperature of 70° C. for 6hours. The reaction mixture was allowed to cool to room temperature, andwas poured into a brine solution and the layers were partitioned. Theaqueous phase was extracted with ethyl acetate (3×125 mL). The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and concentrated. The resulting residue was purified via flash columnchromatography using 0-30% ethyl acetate/hexanes as eluent to afford thetitle compound as a clear liquid (4.93 g, 70%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.68-7.58 (m, 2H), 7.35-7.23 (m, 2H), 3.71 (s, 2H), 3.61 (s,3H), 1.29 (s, 12H); ¹³C NMR (101 MHz, DMSO-d₆) δ 171.29, 137.72, 134.45,128.86, 83.56, 82.79, 51.68, 40.23, 24.62; EIMS m/z 276 ([M]⁺).

Example 3: Preparation of methyl2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(C3)

To a 200 mL round bottomed flask equipped with a magnetic stir bar wasadded 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1)(3.45 g, 11.2 mmol), and methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2)(3.71 g, 13.4 mmol). These reagents were diluted with dioxane (45.0 mL)and water (11.3 mL) and the resulting solution was sparged with nitrogengas for 10 minutes. Tri-tert-butylphosphonium tetrafluoroborate (0.325g, 1.12 mmol), palladium(II)acetate (0.126 g, 0.560 mmol) and cesiumfluoride (3.40 g, 22.4 mmol) were added as solids. The flask was sealedand placed under nitrogen atmosphere. The reaction mixture was heated toan internal temperature of 60° C. The reaction mixture was allowed tocool to room temperature, and was poured into a brine solution and thelayers were partitioned. The aqueous phase was extracted with ethylacetate (3×100 mL). The combined organic layers were dried overanhydrous magnesium sulfate, filtered, and concentrated. The resultingresidue was purified via flash column chromatography using 0-10% ethylacetate/hexanes as eluent to afford the title compound as an off-whitesolid (3.45 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.11-8.04(m, 4H), 7.63 (ddt, J=7.9, 2.1, 1.1 Hz, 2H), 7.48-7.36 (m, 2H), 3.77 (s,2H), 3.64 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −57.02; ESIMS m/z 378([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 3.

Preparation of methyl2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(C4)

The title compound was prepared as described in Example 3 using3-bromo-1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazole (C1a) and methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2)and isolated as a white solid (3.57 g, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ9.42 (s, 1H), 8.18-8.04 (m, 4H), 7.68-7.58 (m, 2H), 7.48-7.38 (m, 2H),3.78 (s, 2H), 3.65 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −85.20 (d,J=2.9 Hz), −86.93; ESIMS m/z 428 ([M+H]⁺).

Preparation of methyl2-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(C5)

The title compound was prepared as described in Example 3 using3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C1b) and methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2)and isolated as a white solid (2.3 g, 81%): ¹H NMR (400 MHz, DMSO-d₆) δ9.53 (s, 1H), 8.23-8.16 (m, 2H), 8.08 (d, J=8.2 Hz, 2H), 8.03-7.96 (m,2H), 7.49-7.38 (m, 2H), 3.78 (s, 2H), 3.65 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −60.82; ESIMS m/z 362 ([M+H]⁺).

Example 4: Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (C6)

To a 100 mL round bottomed flask, equipped with a magnetic stir bar, wasadded methyl2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(C3) (3.45 g, 9.14 mmol) and lithium hydroxide.hydrate (1.15 g, 27.4mmol) as solids. These solids were diluted with tetrahydrofuran (24 mL),methanol (24 mL), and water (12 mL). The reaction was stirred at roomtemperature for 2 hours. The reaction mixture was then concentrated todryness. The resulting solid was then diluted with water, and theresulting suspension was adjusted to pH 2.9. The subsequent precipitatewas extracted with ethyl acetate (5×100 mL). The combined organicextracts were dried over anhydrous magnesium sulfate, filtered, andconcentrated to afford the title compound as a white solid (3.27 g,96%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.40 (s, 1H), 8.15-8.03(m, 4H), 7.63 (dq, J=7.9, 1.0 Hz, 2H), 7.49-7.36 (m, 2H), 3.66 (s, 2H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.98; ESIMS m/z 364 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 4.

Preparation of2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (C7)

The title compound was prepared as described in Example 4 using methyl2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(C4) and isolated as a white solid (3.4 g, 94%): ¹H NMR (400 MHz,DMSO-d₆) δ 12.41 (s, 1H), 9.41 (s, 1H), 8.15-8.02 (m, 4H), 7.67-7.58 (m,2H), 7.47-7.37 (m, 2H), 3.66 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−85.20, −86.92; ESIMS m/z 414 ([M+H]⁺).

Preparation of2-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (C8)

The title compound was prepared as described in Example 4 with methyl2-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(C5) and isolated as a white solid (0.378 g, 98%): ¹H NMR (400 MHz,DMSO-d₆) δ 12.42 (s, 1H), 9.53 (s, 1H), 8.25-8.16 (m, 2H), 8.11-8.04 (m,2H), 7.99 (d, J=8.6 Hz, 2H), 7.47-7.39 (m, 2H), 3.66 (s, 2H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −60.79; ESIMS m/z 348 ([M+H]⁺).

Example 5: Preparation of(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C9)

In a 100 mL round bottomed flask, equipped with a magnetic stir bar,2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (C6) (2.00 g, 5.51 mmol) was diluted with toluene (37 mL). Thentriethylamine (0.767 mL, 5.51 mmol) and diphenyl phosphorazidate (1.19mL, 5.51 mmol) were added. The reaction was allowed to stir for 2.5hours at room temperature. The reaction was then poured in to water andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over anhydrous magnesium sulfate, filtered, and concentrated. Theresulting residue was purified via flash column chromatography using0-10% ethyl acetate/hexanes as eluent to afford the title compound as anoff-white solid (0.800 g, 37%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (d,J=5.9 Hz, 1H), 8.21-7.99 (m, 4H), 7.69-7.57 (m, 2H), 7.57-7.38 (m, 2H),4.70 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.99 (d, J=4.1 Hz); ESIMSm/z 361 ([M+H]⁺) (methyl carbamate).

The following compounds were prepared in accordance to the procedure inExample 5. Physical properties indicate that the isolated products areoften a mixture of the acyl azide and rearranged isocyanate.

Preparation of2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C10)

The title compound was prepared as described in Example 5 using2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (C7) and isolated as a white solid (1.45 g, 46%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.46-9.32 (m, 1H), 8.19-7.97 (m, 4H), 7.68-7.36 (m, 4H), 4.70(s, 1H), 4.34 (d, J=6.1 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −85.23 (d,J=9.8 Hz), −86.95 (d, J=8.0 Hz); ESIMS m/z 442 ([M+H]⁺) (methylcarbamate).

Preparation of2-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(trifluromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C11)

The title compound was prepared as described in Example 5 with2-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (C8) and isolated as a white solid (0.082 g, 25%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.55 (s, 1H), 8.27-8.06 (m, 4H), 7.99 (d, J=8.5 Hz, 2H),7.56-7.49 (m, 1H), 7.44 (dd, J=8.4, 6.9 Hz, 1H), 4.71 (s, 1H), 3.87 (s,1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.80 (d, J=2.9 Hz); ESIMS m/z 345([M+H]⁺).

Example 6: Preparation ofN-[2-(propan-2-yl)phenyl]-N′-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)dicarbonimidothioicdiamide (F14)

In a 20 mL vial, equipped with a magnetic stir bar,(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C9) (0.200 g, 0.515 mmol) was suspended in acetonitrile (3.3mL). The vial was capped and the suspension was heated at 80° C., for 3hours. The suspension was cooled to room temperature and1-(2-isopropylphenyl)thiourea (0.110 g, 0.567 mmol) and cesium carbonate(0.201 g, 0.618 mmol) were charged as solids. This suspension wasstirred at room temperature for 18 hours. The reaction mixture wasfiltered through a glass-fritted funnel. The filtrate was concentratedand the resulting residue was purified via reverse-phase flash columnchromatography (C₁₈ column) using 5-100% acetonitrile/water as eluent toafford the title compound as a light yellow solid (0.104 g, 36%).

The following compounds were prepared in accordance to the procedure inExample 6.

Preparation ofN-(4-{1-[4-(pentafluoroethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)-N′-[2-(propan-2-yl)phenyl]dicarbonimidothioicdiamide (F15)

The title compound was prepared as described in Example 6 using2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C10) and 1-(2-isopropylphenyl)thiourea and isolated as ayellow solid (0.102 g, 36%).

Preparation ofN-[5-methyl-2-(propan-2-yl)phenyl]-N′-(4-{1-[4-(pentafluoroethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)dicarbonimidothioicdiamide (F16)

The title compound was prepared as describe in Example 6 using2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C10) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolatedas a yellow solid (0.130 g, 44%).

Preparation ofN-[5-methyl-2-(propan-2-yl)phenyl]-N′-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)dicarbonimidothioicdiamide (F35)

The title compound was prepared as described in Example 6 using(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C9) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolatedas a yellow solid (0.043 g, 15%).

Example 7: Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(F17)

In a 50 mL round bottomed flask, equipped with a magnetic stir bar,N-[2-(propan-2-yl)phenyl]-N′-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)dicarbonimidothioicdiamide (F14) (0.067 g, 0.12 mmol) and sodium acetate (0.012 g, 0.15mmol) was diluted with acetonitrile (1.2 mL), then methyl 2-bromoacetate(0.013 mL, 0.13 mmol) was added. The flask was fitted with a refluxcondenser and the reaction mixture was heated at 70° C. After 4 hours,an additional aliquot of methyl 2-bromoacetate (0.013 mL, 0.13 mmol) wasadded, and the reaction was allowed to heat for an additional 18 hours.An additional aliquot of methyl 2-bromoacetate (0.013 mL, 0.13 mmol) andsodium acetate (0.012 g, 0.15 mmol) was added, and the reaction wasallowed to heat for an additional 4 hours. The reaction mixture wascooled and diluted with water and extracted with ethyl acetate (50 mL).The organic layer was dried over anhydrous magnesium sulfate, filtered,and concentrated. The resulting residue was purified via reverse-phaseflash column (C₁₈ column) chromatography using 5-100% acetonitrile/wateras eluent to afford the title compound as a white solid (0.036 g, 49%).

The following compounds were prepared in accordance to the procedure inExample 7.

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(F18)

The title compound was prepared as described in Example 7 usingN-(4-{1-[4-(pentafluoroethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)-N′-[2-(propan-2-yl)phenyl]dicarbonimidothioicdiamide (F15) and isolated as an off-white solid (0.043 g, 47%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(F19)

The title compound was prepared as described in Example 7 usingN-[5-methyl-2-(propan-2-yl)phenyl]-N′-(4-{1-[4-(pentafluoroethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)dicarbonimidothioicdiamide (F16) and isolated as a white solid (0.056 g, 46%).

Example 8: Preparation of benzyl 4-bromobenzylcarbamate (C12)

In a 500 mL round bottomed flask, equipped with a magnetic stir bar,(4-bromophenyl)methanaminium chloride (10.0 g, 44.9 mmol) and sodiumhydroxide (4.00 g, 100 mmol) were dissolved in tetrahydrofuran (80 mL)and water (80 mL). The solution was cooled in an ice water bath, andbenzyl chloroformate (7.06 mL, 49.4 mmol) was added dropwise. Thereaction was allowed to stir for 1 hour. The reaction was poured into abrine solution and extracted with ethyl acetate (2×200 mL). The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and concentrated to afford the title compound as a white solid (14.8 g,102%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (t, J=6.0 Hz, 1H), 7.64-7.53 (m,2H), 7.47-7.33 (m, 5H), 7.32-7.20 (m, 2H), 5.10 (s, 2H), 4.23 (d, J=6.2Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 156.33, 139.20, 137.05, 131.10,129.22, 128.33, 127.72, 119.77, 65.42, 43.19; ESIMS m/z 320, 322([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 8.

Preparation of benzyl(1-(4-bromophenyl)-2-methylpropan-2-yl)carbamate(CB1)

The title compound was prepared as described in Example 8 using1-(4-bromophenyl)-2-methylpropan-2-amine and isolated as an off-whitesolid (6.67 g, 81%): mp 82-86° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.27(m, 7H), 6.90 (d, J=8.3 Hz, 2H), 5.09 (s, 2H), 4.47 (s, 1H), 2.94 (s,2H), 1.27 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 150.02, 136.77, 132.13,131.02, 130.49, 128.54, 128.23, 128.15, 120.32, 69.73, 66.09, 53.02,27.41; ESIMS m/z 363 ([M+H]⁺).

Preparation of benzyl(2-(4-bromophenyl)-2-methylpropyl)carbamate (CB2)

The title compound was prepared as described in Example 8 using2-(4-bromophenyl)-2-methylpropan-1-amine and isolated as a tan oil (7.83g, 95%): ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.40 (m, 2H), 7.40-7.27 (m, 5H),7.20 (d, J=8.6 Hz, 2H), 5.05 (s, 2H), 4.48 (t, J=6.1 Hz, 1H), 3.38 (d,J=6.3 Hz, 2H), 1.30 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 156.51, 145.44,136.42, 131.54, 128.53, 128.17, 128.13, 127.87, 120.27, 66.77, 52.39,38.86, 26.36; ESIMS m/z 363 ([M+H]⁺).

Preparation of benzyl(1-(4-bromobenzyl)cyclopropyl)carbamate (CB3)

The title compound was prepared as described in Example 8 using1-(4-bromobenzyl)cyclopropanamine (Ukrorgsyntez Ltd) and isolated as apale yellow solid (3.33 g, 81%): mp 84-86° C.; ¹H NMR (400 MHz, CDCl₃) δ7.51-7.28 (m, 7H), 5.08 (s, 2H), 2.82 (s, 2H), 0.85-0.69 (m, 4H) (NH notobserved); ¹³C NMR (101 MHz, CDCl₃) δ 155.85, 136.52, 131.43, 131.07,128.73, 128.57, 128.51, 128.14, 120.39, 66.47, 40.93, 34.36, 13.54;ESIMS m/z 362 ([M+2]⁺).

Example 9: Preparation of benzyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (C13)

In a 500 mL round bottomed flask, equipped with a magnetic stir bar,benzyl 4-bromobenzylcarbamate (C12) (14.3 g, 44.7 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (12.5 g,49.1 mmol), and potassium acetate (8.77 g, 89.0 mmol) were diluted withdioxane (170 mL). The suspension was sparged with nitrogen gas for 10minutes. The [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(1.63 g, 2.23 mmol) was added as a solid. The flask was placed undernitrogen atmosphere and the reaction mixture was warmed to an internaltemperature of 70° C. for 18 hours. The reaction mixture was cooled toroom temperature, poured into a brine solution and extracted with ethylacetate (3×250 mL). The combined organic layers were dried overanhydrous magnesium sulfate, filtered, and concentrated. The resultingresidue was purified via flash column chromatography using 0-10% ethylacetate/B, where B=1:1 dichloromethane:hexanes, as eluent to afford thetitle compound as an orange solid (11.8 g, 69%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.87 (t, J=6.2 Hz, 1H), 7.71-7.60 (m, 2H), 7.43-7.24 (m, 7H),5.06 (s, 2H), 4.24 (d, J=6.2 Hz, 2H), 1.29 (s, 12H); ¹³C NMR (101 MHz,DMSO-d₆) δ 156.35, 143.18, 137.12, 134.45, 128.31, 127.69, 126.38,83.51, 66.32, 65.37, 64.89, 43.83, 24.62; ESIMS m/z 368 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 9.

Preparation of methyl3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(C13a)

The title compound was prepared as described in Example 9 using methyl3-(3-bromophenyl)propanoate and isolated as a tan solid (9.18 g, 75%):¹H NMR (400 MHz, DMSO-d₆) δ 7.56-7.47 (m, 2H), 7.35 (dt, J=7.7, 1.7 Hz,1H), 7.33-7.23 (m, 1H), 3.57 (s, 3H), 2.86 (t, J=7.6 Hz, 2H), 2.62 (t,J=7.6 Hz, 2H), 1.29 (s, 12H); ¹³C NMR (101 MHz, DMSO-d₆) δ 172.57,139.91, 134.28, 132.18, 131.32, 127.86, 83.54, 51.20, 34.88, 30.10,24.63; EIMS m/z 290.

Preparation of2-(4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)isoindoline-1,3-dione(C13b)

The title compound was prepared as described in Example 9 using2-(4-(3-bromophenyl)butyl)isoindoline-1,3-dione (C57a) and isolated as atan solid (5.50 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.90-7.78 (m, 4H),7.54-7.42 (m, 2H), 7.33-7.23 (m, 2H), 3.59 (t, J=6.5 Hz, 2H), 2.60 (t,J=7.2 Hz, 2H), 1.70-1.48 (m, 4H), 1.28 (s, 12H); ¹³C NMR (101 MHz,DMSO-d₆) δ 167.90, 141.32, 134.33, 131.83, 131.56, 131.40, 127.76,122.93, 83.50, 37.17, 34.52, 28.49, 27.67, 24.64; ESIMS m/z 406([M+H]⁺).

Preparation of2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(CB4)

The title compound was prepared as described in Example 9 using4-bromo-2-methylbenzaldehyde and isolated as a clear and colorless oil(0.623 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 7.78 (d, J=0.8Hz, 2H), 7.70 (s, 1H), 2.67 (s, 3H), 1.36 (s, 12H); ¹³C NMR (101 MHz,CDCl₃) δ 193.08, 139.40, 138.02, 135.89, 132.45, 130.86, 84.28, 24.87,19.37; IR (thin film) cm⁻¹ 2978, 2927, 2728, 1700, 1355, 1194.

Preparation of2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(CB5)

The title compound was prepared as described in Example 9 using4-bromo-2-fluorobenzaldehyde and isolated as a white solid (4.1 g, 67%):¹H NMR (400 MHz, CDCl₃) δ 10.40 (d, J=0.8 Hz, 1H), 7.84 (dd, J=7.6, 6.7Hz, 1H), 7.67 (dt, J=7.6, 0.8 Hz, 1H), 7.58 (dd, J=10.7, 0.9 Hz, 1H),1.36 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ −123.56.

Preparation of methyl2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (CB6)

The title compound was prepared as described in Example 9 using methyl2-(3-bromophenyl)acetate and isolated as a white solid (14.68 g, 97%,80% pure): ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (dt, J=8.4, 1.7 Hz, 2H),7.44-7.28 (m, 2H), 3.71 (s, 2H), 3.62 (s, 3H), 1.30 (s, 12H); ESIMS m/z276 ([M]⁺).

Preparation ofbenzyl(2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamate(CB7)

The title compound was prepared as described in Example 9 usingbenzyl(1-(4-bromophenyl)-2-methylpropan-2-yl)carbamate (CB1) andisolated as a clear oil (6.12 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 7.69(d, J=7.9 Hz, 2H), 7.38 (d, J=5.6 Hz, 5H), 7.10 (d, J=7.9 Hz, 2H), 5.09(s, 2H), 4.51 (s, 1H), 3.00 (s, 2H), 1.34 (s, 12H), 1.29 (s, 6H); ¹³CNMR (101 MHz, CDCl₃) δ 152.73, 141.11, 136.77, 134.45, 129.95, 128.52,128.10, 128.06, 83.71, 66.09, 54.47, 53.21, 27.43, 24.88; ESIMS m/z 410([M+H]⁺).

Preparation ofbenzyl(2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate(CB8)

The title compound was prepared as described in Example 9 usingbenzyl(2-(4-bromophenyl)-2-methylpropyl)carbamate (CB2) and isolated asa pale yellow oil (8.47 g, 95%): ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.73 (m,2H), 7.32 (dtd, J=14.5, 7.4, 6.8, 2.7 Hz, 7H), 5.04 (s, 2H), 4.50-4.37(m, 1H), 3.41 (d, J=6.3 Hz, 2H), 1.34 (s, 12H), 1.33 (s, 6H); ¹³C NMR(101 MHz, CDCl₃) δ 156.56, 149.64, 136.52, 135.07, 131.54, 128.48,128.06, 127.87, 125.34, 83.77, 66.66, 52.46, 39.15, 26.36, 24.86; ESIMSm/z 410 ([M+H]⁺).

Preparation ofbenzyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopropyl)carbamate(CB9)

The title compound was prepared as described in Example 9 usingbenzyl(1-(4-bromobenzyl)cyclopropyl)carbamate (CB3) and purified usingethyl acetate/hexanes as eluent; isolated as a white solid (2.53 g,67%): mp 102-104° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.63 (m, 2H),7.51-7.28 (m, 5H), 7.16 (d, J=7.5 Hz, 2H), 5.08 (s, 2H), 4.90 (s, 1H),2.89 (s, 2H), 1.34 (s, 12H), 0.80 (s, 4H); ESIMS m/z 408 ([M+H]⁺).

Example 10: Preparation of benzyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylcarbamate(C14)

In a 50 mL round bottomed flask, equipped with a magnetic stir bar,3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (1.0 g,3.3 mmol), benzyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (C13)(1.3 g, 3.6 mmol), bistriphenylphosphine dichloropalladium(II) (0.120 g,0.171 mmol), and potassium phosphate (1.38 g, 6.49 mmol) were charged assolids. The flask was sealed and placed under nitrogen atmosphere.Dioxane (17.3 mL) and water (4.3 mL) were added. The reaction was warmedto an internal temperature of 65° C. for 18 hours. The reaction mixturewas cooled to room temperature, poured into a brine solution andextracted with ethyl acetate (3×75 mL). The combined organic layers weredried over anhydrous magnesium sulfate, filtered, and concentrated. Theresulting residue was purified via flash column chromatography using0-50% ethyl acetate/hexanes as eluent to afford the title compound as awhite solid (0.850 g, 56%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H),8.17-8.00 (m, 4H), 7.91 (t, J=6.2 Hz, 1H), 7.72-7.59 (m, 2H), 7.46-7.12(m, 7H), 5.07 (s, 2H), 4.29 (d, J=6.1 Hz, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −56.96; ESIMS m/z 469 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 10.

Preparation of benzyl4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylcarbamate(C15)

The title compound was prepared as described in Example 10 using3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C1b), benzyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (C13),tri-tert-butylphosphonium tetrafluoroborate, palladium(II)acetate, andcesium fluoride and isolated as a white solid (0.846 g, 36%): ¹H NMR(400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.28-8.14 (m, 2H), 8.16-8.04 (m, 2H),8.04-7.95 (m, 2H), 7.92 (t, J=6.2 Hz, 1H), 7.49-7.13 (m, 7H), 5.07 (s,2H), 4.29 (d, J=6.2 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.79; ESIMSm/z 453 ([M+H]⁺).

Preparation of methyl3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CA1)

The title compound was prepared as described in Example 10 using3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1), methyl3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(C13a), and[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) at 80°C. and isolated as a dark orange solid (9.86 g, 91%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.40 (s, 1H), 8.12-8.03 (m, 2H), 8.01-7.91 (m, 2H), 7.66-7.58(m, 2H), 7.49-7.40 (m, 1H), 7.34 (dt, J=7.8, 1.6 Hz, 1H), 3.59 (s, 3H),2.95 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −57.01; ESIMS m/z 392 ([M+H]⁺).

Preparation of2-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)isoindoline-1,3-dione(CA2)

The title compound was prepared as described in Example 10 using3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1),2-(4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)isoindoline-1,3-dione(C13b), and[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) at 75°C. and isolated as a dark orange solid (5.48 g, 82%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.39 (s, 1H), 8.13-8.04 (m, 2H), 7.96-7.89 (m, 2H), 7.88-7.77(m, 4H), 7.67-7.57 (m, 2H), 7.45-7.38 (m, 1H), 7.31 (dt, J=7.7, 1.5 Hz,1H), 3.69-3.53 (m, 2H), 2.70 (t, J=6.8 Hz, 2H), 1.64 (dq, J=6.6, 3.1 Hz,4H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 507 ([M+H]⁺).

Preparation of3-(2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB10)

The title compound was prepared as described in Example 10 using3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C52)with tetrakis(triphenylphosphine)palladium(0) as catalyst, sodiumcarbonate as base and heating to 100° C. for 3 hours; isolated as anorange solid (2.18 g, 57%, 79% pure): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s,1H), 8.15-8.06 (m, 2H), 7.80 (dd, J=9.0, 2.3 Hz, 2H), 7.50 (d, J=8.4 Hz,2H), 7.39 (ddd, J=8.0, 2.5, 1.3 Hz, 2H), 6.28-6.21 (m, 1H), 2.46 (ddt,J=6.3, 4.1, 2.0 Hz, 2H), 2.24 (dtd, J=6.3, 3.8, 1.8 Hz, 2H), 1.85-1.75(m, 2H), 1.71-1.63 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −58.03; ESIMSm/z 386 ([M+H]⁺).

Preparation of methyl2-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(CB11)

The title compound was prepared as described in Example 10 using methyl2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (CB6)using [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)as catalyst, sodium carbonate as base and heating to 75° C. for 30hours; isolated as a pink solid (4.96 g, 72%): ¹H NMR (400 MHz, DMSO-d₆)δ 9.41 (s, 1H), 8.12-8.05 (m, 2H), 8.05-7.98 (m, 2H), 7.61 (ddt, J=7.9,2.0, 1.0 Hz, 2H), 7.47 (td, J=7.6, 0.6 Hz, 1H), 7.38 (ddd, J=7.6, 2.0,1.2 Hz, 1H), 3.81 (s, 2H), 3.64 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−57.06; ESIMS m/z 378 ([M+H]⁺).

Example 10a: Preparation of tert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylcarbamate(C15a)

In a 20 mL vial(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetylazide/2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methylisocyanate (C9) (0.205 g, 0.528 mmol) was diluted with tert-butanol(10.0 mL, 105 mmol). The solution was heated to 80° C. overnight. Thereaction was cooled and poured into a brine solution and extracted withethyl acetate (4×). The combined organics were dried over magnesiumsulfate, filtered, and concentrated. The resulting residue was purifiedby flash column chromatography using 0-40% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent provided the title compound as awhite solid (0.0890 g, 39%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H),8.15-8.01 (m, 4H), 7.63 (dp, J=7.9, 1.0 Hz, 2H), 7.47 (t, J=6.1 Hz, 1H),7.42-7.35 (m, 2H), 4.20 (d, J=6.2 Hz, 2H), 1.41 (s, 9H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −56.96; ESIMS m/z 435 ([M+H]⁺).

Example 11: Preparation of(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16)

In a 200 mL round bottomed flask equipped with a magnetic stir bar,benzyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylcarbamate(C14) (0.850 g, 1.82 mmol) was diluted with a solution of hydrogenbromide in acetic acid (33 wt %, 15.0 mL, 1.82 mmol). The suspension wasallowed to stir for 1 hour. Diethyl ether (150 mL) was added, and thereaction mixture was stirred for an additional 30 minutes. The resultingprecipitate was collected via filtration and treated with aqueous sodiumhydroxide. The resulting suspension was extracted with ethyl acetate(3×75 mL). The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated to afford the titlecompound as a white solid (0.448 g, 74%): ¹H NMR (400 MHz, DMSO-d₆) δ9.39 (s, 1H), 8.07 (dd, J=10.6, 8.6 Hz, 4H), 7.69-7.56 (m, 2H), 7.48 (d,J=8.2 Hz, 2H), 3.79 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.98; ESMISm/z 318 ([M+H]⁺) (—NH₂).

The following compounds were prepared in accordance to the procedure inExample 11.

Preparation of(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(CA3)

The title compound was prepared as described in Example 11 from benzyl4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylcarbamate(C15) and isolated as a tan solid (4.67 g, 79%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.52 (s, 1H), 8.21 (d, J=8.3 Hz, 2H), 8.09 (d, J=7.9 Hz, 2H),8.00 (d, J=8.4 Hz, 2H), 7.51 (d, J=7.9 Hz, 2H), 3.82 (s, 2H).

Example 12: Preparation ofN-[5-methyl-2-(propan-2-yl)phenyl]-N′-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}benzyl)dicarbonimidothioicdiamide (F35)

In a 200 mL round bottomed flask equipped with a magnetic stir bar,(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) (0.448 g, 1.34 mmol) was diluted with tetrahydrofuran (9.0 mL). Tothe suspension was added triphosgene (0.398 g, 1.34 mmol) andtriethylamine (0.374 mL, 2.68 mmol). The resulting suspension wasstirred for 1 hour at room temperature. UPLC analysis of amethanol-quenched aliquot shows a mixture of the methyl carbamate andthe isocyanate. To the reaction mixture1-(2-isopropyl-5-methylphenyl)thiourea (0.279 g, 1.34 mmol) and cesiumcarbonate (0.480 g, 1.47 mmol) were added. The reaction mixture wasallowed to stir at room temperature for 18 hours. An additional portionof 1-(2-isopropyl-5-methylphenyl)thiourea (0.279 g, 1.34 mmol) andcesium carbonate (0.480 g, 1.47 mmol) were added and the reactionmixture was warmed to an internal temperature of 60° C. for 1 hour. Thereaction mixture was poured into water and extracted with ethyl acetate(3×75 mL). The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated. The resulting residue waspurified by reverse-phase flash column (C₁₈ column) chromatography using5-100% acetonitrile/water as eluent followed by flash columnchromatography using 0-100% ethyl acetate/hexanes as eluent to give thetitle compound as a white solid (0.007 g, 0.9%).

Example 13: Preparation of (E)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C17)

To an oven-dried 2 L three-necked round bottomed flask equipped with astirring bar was added sodium hydride (60% oil immersion, 7.20 g, 180mmol) as a solid that was pre-weighed into a 25-mL vial. This wasdiluted with anhydrous tetrahydrofuran (1 L) under nitrogen, and thesolution was stirred in an ice bath. Ethyl 2-(diethoxyphosphoryl)acetate(30.0 mL, 151 mmol) was added dropwise in portions over 20 minutes, andthe reaction was stirred at 0° C. for an additional 2 hours.4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(50.0. g, 150 mmol) was added in solid portions over 20 minutes, and thereaction turned orange. After stirring for 30 minutes, the ice bath wasremoved and the reaction was warmed to room temperature over 1 hour. Thereaction was quenched with slow addition of saturated aqueous ammoniumchloride (500 mL) and allowed to stand at room temperature overnight.The biphasic reaction mixture was diluted with water and extracted with1:1 ethyl acetate/hexanes (3×). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated to afford thetitle compound as an orange solid (61.4 g, 100%): mp 135-137° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 7.85-7.77 (m,2H), 7.73 (d, J=16.0 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz,2H), 6.51 (d, J=16.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz,3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 404 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 13.

Preparation of (E)-ethyl3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C18)

The title compound was prepared as described in Example 13 from4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde andisolated as a white solid (2.08 g, 100%): mp 149-153° C.; ¹H NMR (400MHz, CDCl₃) δ 8.59 (s, 1H), 8.32-8.16 (m, 2H), 7.89-7.77 (m, 2H), 7.73(d, J=16.0 Hz, 1H), 7.68-7.58 (m, 2H), 7.47-7.35 (m, 2H), 6.51 (d,J=16.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H); ¹⁹F NMR(376 MHz, CDCl₃) δ −85.89, −87.85, −87.86; ESIMS m/z 454 ([M+H]⁺).

Preparation of (E)-ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate(CA4)

The title compound was prepared as described in Example 13 from1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanone(C25) and ethyl 2-(diethoxyphosphoryl)propanoate and isolated as a paleyellow solid (0.480 g, 27%): mp 68-70° C.; ¹H NMR (400 MHz, CDCl₃) δ8.58 (s, 1H), 8.22-8.13 (m, 2H), 7.86-7.77 (m, 2H), 7.40 (dt, J=8.0, 1.0Hz, 2H), 7.31-7.25 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.29 (q, J=1.5 Hz,3H), 1.80 (q, J=1.5 Hz, 3H), 1.36 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.03; ¹³C NMR (101 MHz, CDCl₃) δ 169.91, 163.24, 148.37,144.86, 144.66, 141.54, 135.56, 129.10, 127.77, 126.57, 125.32, 122.42,121.18, 60.45, 22.94, 17.45, 14.32; ESIMS m/z 432 ([M+H]⁺).

Preparation of (E)-ethyl3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(CA5)

The title compound was prepared as described in Example 13 from4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde andisolated as a pale yellow solid (4.02 g, 100%): mp 135-140° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.23 (d, J=8.3 Hz, 2H), 7.95-7.88 (m,2H), 7.81 (dt, J=8.3, 0.7 Hz, 2H), 7.73 (d, J=16.0 Hz, 1H), 7.69-7.56(m, 2H), 6.51 (d, J=16.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.41-1.31 (m,3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.50; ESIMS m/z 388 ([M+H]⁺).

Preparation of (E)-ethyl3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(CB12)

The title compound was prepared as described in Example 13 from2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(CB35) and isolated as a white solid (1.16 g, 98%): mp 157-160° C.; ¹HNMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.10-7.96 (m, 3H), 7.84-7.76 (m,2H), 7.68 (d, J=8.1 Hz, 1H), 7.40 (dt, J=8.1, 1.0 Hz, 2H), 6.44 (d,J=15.9 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.53 (s, 3H), 1.36 (t, J=7.1 Hz,3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 418 ([M+H]⁺).

Preparation of (E)-ethyl3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(CB13)

The title compound was prepared as described in Example 13 from2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(CB36) and isolated as a light orange solid (1.1 g, 92%): ¹H NMR (400MHz, CDCl₃) δ 8.58 (s, 1H), 8.03-7.91 (m, 2H), 7.80 (d, J=9.0 Hz, 2H),7.65 (t, J=7.8 Hz, 1H), 7.40 (dt, J=8.1, 1.0 Hz, 2H), 6.63 (s, 1H), 6.59(s, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H); ESIMS m/z 422([M+H]⁺).

Preparation of (E/Z)-ethyl2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)butanoate(CB14)

The title compound was prepared as described in Example 13 from4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde andethyl 2-(diethoxyphosphoryl)butanoate; isolated as a yellow solid (4.36g, 102%) as mixture of E and Z isomers: ¹H NMR (400 MHz, CDCl₃) δ8.66-8.53 (m, 1H), 8.29-8.10 (m, 2H), 7.86-7.66 (m, 3H), 7.58-7.48 (m,2H), 7.44-7.31 (m, 2H), 4.23 (dq, J=53.7, 7.1 Hz, 2H), 2.70-2.42 (m,2H), 1.42-1.09 (m, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 432([M+H]⁺).

Example 14: Preparation of ethyl2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarboxylate(C19)

To an oven-dried round bottomed flask was added sodium hydride (60% oilimmersion, 0.380 g, 9.50 mmol) and anhydrous dimethyl sulfoxide (30 mL).Gas evolution occurred, and the solution was stirred at room temperaturefor 15 minutes. Trimethylsulfoxonium iodide (2.10 g, 9.54 mmol) wasadded, the flask neck was rinsed with anhydrous dimethyl sulfoxide (5mL), and the reaction was stirred for 15 minutes. To the reaction wasadded (E)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C17) (3.22 g, 7.98 mmol) as a solid. The reaction was stirred at roomtemperature for 30 minutes, and then quenched with water and extractedwith 1:1 ethyl acetate/hexanes (2×). The combined organic layers werewashed with water (3×), dried over anhydrous sodium sulfate, filtered,and concentrated to afford the title compound as a yellow oil (1.50 g,41%): ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.10 (d, J=8.4 Hz, 2H),7.80 (d, J=9.1 Hz, 2H), 7.39 (dd, J=6.6, 5.9 Hz, 2H), 7.20 (d, J=8.3 Hz,2H), 4.19 (dt, J=14.0, 7.0 Hz, 2H), 2.64-2.52 (m, 2H), 1.97 (ddd, J=8.5,5.3, 4.2 Hz, 1H), 1.71-1.61 (m, 1H), 1.42-1.32 (m, 1H), 1.29 (t, J=7.1Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 418 ([M+H]⁺).

Example 15: Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarboxylicacid (C20)

To ethyl2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-cyclopropane-carboxylate(C19) (1.50 g, 3.59 mmol) in methanol (24 mL) was added sodium hydroxide(2 N, 7.20 mL, 14.4 mmol) and stirred at room temperature for 4 hours.The reaction was acidified with hydrogen chloride (2 N) and the methanolwas evaporated off under vacuum. The aqueous solution was extracted withethyl acetate (2×), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford the title compound as a yellow oil (1.62 g, 98%):¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.13-8.08 (m, 2H), 7.83-7.77 (m,3H), 7.40 (t, J=5.9 Hz, 4H), 7.22 (d, J=8.3 Hz, 2H), 2.65 (ddd, J=6.7,5.3, 2.8 Hz, 2H), 2.03-1.95 (m, 1H), 1.76-1.66 (m, 2H), 1.47 (ddd,J=8.4, 6.6, 4.7 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z390 ([M+H]⁺).

Example 16: Preparation2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21)

To2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-cyclo-propanecarboxylicacid (C20) (2.49 g, 6.40 mmol) in toluene (30 mL) was addedtriethylamine (2.20 mL, 16.0 mmol), followed by diphenyl phosphorazidate(1.70 mL, 8.00 mmol). The yellow solution was stirred overnight at roomtemperature. The reaction was quenched with water and saturated aqueoussodium bicarbonate, extracted with 1:1 ethyl acetate/hexanes (2×), driedover anhydrous sodium sulfate, and filtered. The crude compound wasadsorbed onto silica gel and purified by flash column chromatographyusing 0-100% ethyl acetate/hexanes as eluent to afford the titlecompound as a yellow oil (1.94 g, 73%): ¹H NMR (400 MHz, CDCl₃) δ 8.56(s, 1H), 8.16-8.03 (m, 2H), 7.83-7.72 (m, 2H), 7.44-7.34 (m, 2H), 7.20(d, J=8.2 Hz, 2H), 2.70 (ddd, J=9.3, 6.8, 4.1 Hz, 1H), 1.98 (ddd, J=8.4,5.3, 4.1 Hz, 1H), 1.78 (dt, J=9.4, 5.0 Hz, 1H), 1.53 (ddd, J=8.3, 6.8,4.7 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03.

Example 17: Preparation ofN-[2-(propan-2-yl)phenyl]-N′-,2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F22)

A solution of(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21) (0.250 g, 0.600 mmol) in 1,2-dichloroethane (3 mL) washeated at 80° C. for 3 hours. The reaction was cooled and2-(isopropylphenyl)thiourea (0.129 g, 0.660 mmol) and cesium carbonate(0.443 g, 1.36 mmol) were added. The reaction mixture was stirred atroom temperature overnight, and then diluted with ethyl acetate andwashed with water. The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated. The crude compound was loaded ontoa Celite® cartridge with dichloromethane and purified by flash columnchromatography using 0-40% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent to afford the title compound as awhite solid (0.108 g, 31%).

The following compounds were prepared in accordance to the procedure inExample 17.

Preparation ofN-(2-propylphenyl)-N-[(2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F23)

The title compound was prepared as described in Example 17 using(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21) and 1-(2-propylphenyl)thiourea and isolated as an off-whitesolid (0.059 g, 18%).

Preparation ofN-(2-ethyl-6-methylphenyl)-N-[2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F24)

The title compound was prepared as described in Example 17 using(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) and isolatedas a white solid (0.105 g, 33%).

Preparation ofN-(2,6-dimethylphenyl)-N-[(2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F25)

The title compound was prepared as described in Example 17 using(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21) and 1-(2,6-dimethylphenyl)thiourea and isolated as a whitesolid (0.105 g, 29%).

Preparation ofN-(4-methoxy-2-methylphenyl)-N′-[(2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F26)

The title compound was prepared as described in Example 17 using(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as awhite oily solid (0.009 g, 3%).

Preparation ofN-(2-ethyl-5-methylphenyl)-N-[2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F27)

The title compound was prepared as described in Example 17 using(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21) and 1-(2-ethyl-5-methylphenyl)thiourea (CA41) and isolatedas an off-white solid (0.069 g, 22%).

Example 18: Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)urea(F29)

A solution ofN-[2-(propan-2-yl)phenyl]-N′-,2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F22) (0.082 g, 0.14 mmol), methyl 2-bromoacetate (0.020 mL,0.21 mmol), and sodium acetate (0.027 g, 0.33 mmol) in ethanol (1.8 mL)was heated at 65° C. overnight. The reaction was cooled, loaded onto aCelite® cartridge, and purified by flash column chromatography using0-40% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent toafford the title compound as an off-white solid (0.061 g, 68%).

The following compounds were prepared in accordance to the procedure inExample 18.

Preparation of(Z)-1-(4-oxo-3-(2-propylphenyl)thiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)urea(F30)

The title compound was prepared as described in Example 18 fromN-(2-propylphenyl)-N-[(2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F23) and isolated as an off-white oily solid (0.026 g, 68%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)urea(F31)

The title compound was prepared as described in Example 18 fromN-(2-ethyl-6-methylphenyl)-N-[2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F24) and isolated as an oil (0.006 g, 8%).

Preparation of(Z)-1-(3-(2,6-dimethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)urea(F32)

The title compound was prepared as described in Example 18 fromN-(2,6-dimethylphenyl)-N-[(2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F25) and isolated as an oil (0.006 g, 7%).

Preparation of(Z)-1-(3-(2-ethyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)urea(F33)

The title compound was prepared as described in Example 18 fromN-(2-ethyl-5-methylphenyl)-N-[2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F27) and isolated as a yellow solid (0.035 g, 71%).

Example 19: Preparation ofN-[5-methyl-2-(propan-2-yl)phenyl]-N-[2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)cyclopropyl]dicarbonimidothioicdiamide (F28) and(Z)-1-(3-(2-isopropyl-5-methylphenyl)thiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)urea(F34)

A solution of(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropanecarbonylazide (C21) (0.210 g, 0.510 mmol) in 1,2-dichloroethane (2.5 mL) washeated at 80° C. for 3 hours. The reaction was cooled to roomtemperature and 1-(2-isopropyl-5-methylphenyl)thiourea (0.127 g, 0.610mmol) and cesium carbonate (0.345 g, 1.06 mmol) were added. The reactionmixture was stirred at room temperature overnight. The reaction wasdiluted with ethyl acetate and washed with water. The aqueous layer wasextracted with ethyl acetate (2×), the organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated. The crude materialwas loaded onto a Celite® cartridge with dichloromethane and purified byflash column chromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent to afford the title compound (F28) asa white solid (0.025 g, 8%) and the title compound (F34) as a yellow oil(0.028 g, 8%).

Example 20: Preparation of(E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylicacid (C22)

To (E)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C17) (1.95 g, 4.83 mmol) in methanol (25 mL) was added sodium hydroxide(2 N, 10 mL, 20.0 mmol) and the solution was stirred at room temperatureovernight. The methanol was evaporated off under reduced pressure, thereagents were diluted with acetonitrile, and additional sodium hydroxide(2 N, 20 mL, 40.0 mmol) was added. The reaction was stirred at roomtemperature for 5 hours and then acidified with hydrogen chloride (2 N).The white precipitate was vacuum-filtered to afford the title compoundas a white solid (1.72 g, 94%): mp 239-241° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 12.48 (s, 1H), 9.44 (s, 1H), 8.14 (d, J=8.4 Hz, 2H),8.12-8.05 (m, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.69-7.59 (m, 3H), 6.61 (d,J=16.0 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z 376([M+H]⁺).

Example 21: Preparation of(E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acryloylazide (C23)

To(E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylicacid (C22) (1.72 g, 4.59 mmol) in isopropanol (15.3 mL) was diphenylphosphorazidate (1.3 mL, 6.03 mmol) and triethylamine (0.96 mL, 6.89mmol) and stirred at room temperature for 6 hours. The white precipitatefor filtered, rinsed with isopropanol, and dried to afford the titlecompound as a white solid (1.46 g, 78%): mp 106° C. (dec); ¹H NMR (400MHz, CDCl₃) δ 8.59 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 7.86-7.73 (m, 3H),7.66 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.52 (t, J=14.6 Hz, 1H);¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 401 ([M+H]⁺).

Example 22: Preparation ofN-[2-(propan-2-yl)phenyl]-N′-[(E)-2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethenyl]dicarbonimidothioicdiamide (F11)

(E)-3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acryloylazide (C23) (0.175 g, 0.440 mmol) in anhydrous acetonitrile (2.2 mL) washeated at 80° C. for 2 hours. The reaction was cooled and1-(2-isopropylphenyl)thiourea (0.110 g, 0.570 mmol) and cesium carbonate(0.214 g, 0.660 mmol) were added. The reaction mixture was stirred atroom temperature overnight, and then diluted with ethyl acetate andwashed with water. The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated. The crude material was loaded ontoa Celite® cartridge and purified by flash column chromatography using0-40% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent toafford the title compound as a yellow solid (0.0800 g, 32%).

Example 23: Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-((E)-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)styryl)urea(F12)

ToN-[2-(propan-2-yl)phenyl]-N-[(E)-2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethenyl]dicarbonimidothioicdiamide (F11) (0.056 g, 0.099 mmol) and sodium acetate (0.020 g, 0.24mmol) in ethanol (0.86 mL) was added methyl 2-bromoacetate (0.012 mL,0.12 mmol), and the solution was heated at 65° C. for 2 hours. Thereaction mixture was loaded directly onto a Celite® cartridge andpurified by flash column chromatography using 0-50% ethyl acetate/B,where B=1:1 dichloromethane/hexanes, as eluent to afford the titlecompound as an orange solid (0.052 g, 84%).

Example 24: Preparation of1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanol(C24)

To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(8.49 g, 25.5 mmol) in anhydrous tetrahydrofuran (102 mL) in dryice/acetone bath was added methylmagnesium bromide (1 M in butyl ether,25.5 mL, 25.5 mmol). The solution was then warmed to room temperatureand stirred overnight. The reaction was acidified with hydrogen chloride(2 N, 10 mL) until pH 2, diluted with water, and extracted with ethylacetate (2×). The organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated to afford the title compound as anorange liquid (8.80 g, 94%): ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H),8.27-8.11 (m, 2H), 7.90-7.68 (m, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.39 (d,J=8.3 Hz, 2H), 4.98 (q, J=6.5 Hz, 1H), 1.54 (d, J=6.5 Hz, 3H); ¹⁹F NMR(376 MHz, CDCl₃) δ −58.03; ESIMS m/z 350 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 24.

Preparation of1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-ol(CA6)

The title compound was prepared as described in Example 24 from4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde andethylmagnesium bromide and isolated as a yellow oil (5.00 g, 100%): ¹HNMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.20-8.12 (m, 2H), 7.85-7.76 (m,2H), 7.50-7.44 (m, 2H), 7.39 (dq, J=8.0, 1.0 Hz, 2H), 4.68 (t, J=6.5 Hz,1H), 1.93-1.75 (m, 2H), 1.59 (s, 1H), 0.95 (t, J=7.4 Hz, 3H); ¹⁹F NMR(376 MHz, CDCl₃) δ −58.03; ESIMS m/z 364 ([M+H]⁺).

Example 25: Preparation of1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanone(C25)

To1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanol(C24) (8.80 g, 25.2 mmol) in dichloromethane (168 mL) and dimethylsulfoxide (84 mL) was added triethylamine (17 mL) and stirred in an icebath. Pyridine-sulfur trioxide (16.0 g, 101 mmol) was added in twoportions. The reaction was warmed to room temperature over 3 hours,diluted with dichloromethane, and washed with water. The aqueous layerwas extracted one additional time with dichloromethane. The combineddichloromethane layers were washed with water, dried over anhydroussodium sulfate, filtered, and adsorbed onto silica gel. Purification byflash column chromatography using 0-100% ethyl acetate/hexanes as eluentprovided the title compound as a white solid (6.71 g, 73%): mp140-141.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 8.33-8.27 (m,2H), 8.11-8.05 (m, 2H), 7.85-7.78 (m, 2H), 7.41 (dd, J=9.0, 0.8 Hz, 2H),2.66 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.01; ESIMS m/z 348 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 25.

Preparation of1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-one(CA7)

The title compound was prepared from1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-ol(CA6) and isolated as a white solid (4.1 g, 63%, 75% pure): ¹H NMR (400MHz, CDCl₃) δ 8.60 (s, 1H), 8.32-8.25 (m, 2H), 8.11-8.05 (m, 2H), 7.82(dd, J=8.9, 1.9 Hz, 2H), 7.41 (dt, J=8.1, 1.0 Hz, 2H), 3.06 (q, J=7.2Hz, 2H), 1.26 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02;ESIMS m/z 362 ([M+H]⁺).

Example 26: Preparation of (E)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate(C26) and (Z)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate(C27)

To an oven-dried round bottomed flask was added sodium hydride (60% oilsuspension, 0.880 g, 1.53 mmol) and anhydrous tetrahydrofuran (36 mL)and the solution was stirred under nitrogen in an ice bath. Ethyl2-(diethoxyphosphoryl)acetate (3.4 mL, 17.3 mmol) was added dropwise andstirred for 30 minutes in an ice bath.1-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanone(C25) (5.00 g, 14.4 mmol) was added in solid portions to the solution,in which the solution turned yellow. The reaction was warmed to roomtemperature overnight, quenched with saturated aqueous ammoniumchloride, and extracted with diethyl ether (2×). The organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude material was loaded onto a Celite® cartridge with dichloromethane,and the cartridge was dried in vacuum oven. Purification byreverse-phase flash column chromatography using 0-100%acetonitrile/water as eluent afforded title compound (C26) as a whitesolid (4.06 g, 67%): mp 109-110.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.58(s, 1H), 8.28-8.16 (m, 2H), 7.88-7.77 (m, 2H), 7.66-7.55 (m, 2H),7.45-7.34 (m, 2H), 6.22 (d, J=1.3 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 2.62(d, J=1.3 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ−58.02; ESIMS m/z 418 ([M+H]⁺), and title compound (C27) as a whitesolid (1.08 g, 18%): mp 83-86° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s,1H), 8.22-8.15 (m, 2H), 7.86-7.76 (m, 2H), 7.39 (dd, J=9.0, 0.8 Hz, 2H),7.36-7.31 (m, 2H), 5.95 (d, J=1.4 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 2.22(d, J=1.4 Hz, 3H), 1.09 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ−58.03; ESIMS m/z 418 ([M+H]⁺).

Example 27: Preparation of(E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoicacid (C28)

To (E)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate(C26) (1.30 g, 3.10 mmol) in methanol (10 mL) was added sodium hydroxide(2 N, 12.3 mL, 24.6 mmol) and stirred at room temperature overnight.Additional sodium hydroxide (2 N) was added and the reaction was heatedto 50° C. for 3 days. The reaction was acidified with hydrogen chloride(2 N) and the white precipitate was collected by vacuum filtration toafford the title compound as a white solid (1.16 g, 95%): mp 234-238°C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 9.43 (s, 1H), 8.14 (d,J=8.6 Hz, 2H), 8.09 (d, J=9.1 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.68-7.53(m, 2H), 6.22 (d, J=1.3 Hz, 1H), 2.54 (d, J=1.3 Hz, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −56.96; ESIMS m/z 390 ([M+H]⁺).

Example 28: Preparation of(E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoylazide (C29)

To(E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoicacid (C28) (1.14 g, 2.93 mmol) in isopropanol (9.8 mL) was addedtriethylamine (0.53 mL, 3.81 mmol) and diphenyl phosphorazidate (0.68mL, 3.23 mmol). The reaction was stirred at room temperature overnight.The white precipitate was vacuum-filtered and dried in a vacuum oven toafford the title compound as a white solid (0.978 g, 80%): ¹H NMR (400MHz, CDCl₃) δ 8.59 (s, 1H), 8.25-8.19 (m, 2H), 7.85-7.78 (m, 2H),7.65-7.58 (m, 2H), 7.44-7.37 (m, 2H), 6.16 (d, J=1.3 Hz, 1H), 2.68 (d,J=1.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 387 ([M+H]⁺)(isocyanate).

Example 29: Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-((E)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)prop-1-en-1-yl)urea(F13)

(E)-3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoylazide (C29) (0.28 g, 0.68 mmol) in acetonitrile (3.4 mL) was heated at80° C. for 3 hours. The reaction was cooled and1-(2-isopropylphenyl)thiourea (0.14 g, 0.74 mmol) and cesium carbonate(0.28 g, 0.86 mmol) were added. The reaction was stirred at roomtemperature overnight, diluted with ethyl acetate and washed with water.The organic layers were dried over anhydrous sodium sulfate, filtered,and concentrated to provide an orange foam. To the crude material (0.39g) was added sodium acetate (0.082 g, 1.0 mmol), ethanol (3.4 mL), andmethyl 2-bromoacetate (0.10 mL, 1.0 mmol). The reaction mixture washeated at 65° C. for 3 hours. The reaction was cooled, diluted withethyl acetate, and washed with water. The organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated. The crude compoundwas loaded onto a Celite® cartridge with dichloromethane and purified byflash column chromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent to afford the title compound as anorange sticky gum (0.16 g, 37%).

The following compounds were prepared in accordance to the procedure inExample 29.

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB7)

The title compound was prepared as described in Example 29, using3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB20) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) andheating to a temperature of 60° C. after methyl 2-bromoacetate wasadded; purified via reverse phase chromatography and isolated as a pinksolid (0.033 g, 17%).

Preparation of(Z)-1-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)-3-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)urea(FB9)

The title compound was prepared as described in Example 29, using3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB21) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) andheating to a temperature of 60° C. when methyl 2-bromoacetate added;purified via reverse phase chromatography and isolated as a pink solid(0.023 g, 11%).

Example 30: Preparation of ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(C30)

A mixture of (E)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C17) (1.08 g, 2.68 mmol) and palladium on carbon (10%, 0.285 g, 0.270mmol) in ethyl acetate (10.7 mL) was stirred at room temperature. Thereaction flask was evacuated under vacuum, backfilled with nitrogen,evacuated under vacuum again, and then backfilled with hydrogen byballoon (1 atm). The reaction was stirred at room temperature overnightand then filtered through a pad of Celite® and concentrated to affordthe title compound as a gray oil that solidified to a wax upon standingat room temperature (0.999 g, 87%): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s,1H), 8.14-8.07 (m, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.42-7.36 (m, 2H), 7.32(d, J=8.4 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 2.67(t, J=7.8 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ−58.03; ESIMS m/z 406 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 30.

Preparation of ethyl3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(C31)

The title compound was prepared from (E)-ethyl3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C18) and isolated as an off-white fluffy solid (2.00 g, 97%): mp109-110.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=1.3 Hz, 1H),8.14-8.08 (m, 2H), 7.84-7.77 (m, 2H), 7.42-7.36 (m, 2H), 7.35-7.29 (m,2H), 4.14 (q, J=7.2 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 2.67 (dd, J=8.3,7.2 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.90,−87.85; ESIMS m/z 456 ([M+H]⁺).

Preparation of ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoate(CA8)

The title compound was prepared from (E)-ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate(CA4) and isolated as a yellow oil (0.495 g, 100%): ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 1H), 8.12-8.05 (m, 2H), 7.83-7.73 (m, 2H), 7.38 (dq,J=8.0, 1.1 Hz, 2H), 7.34-7.29 (m, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.11 (dq,J=8.8, 7.1 Hz, 1H), 2.69 (dd, J=8.6, 6.9 Hz, 1H), 1.31 (d, J=7.1 Hz,3H), 1.21 (d, J=6.9 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.03; ESIMS m/z 434 ([M+H]⁺).

Preparation of ethyl3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CA9)

The title compound was prepared from (E)-ethyl3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(CA5) and isolated as a white solid (3.88 g, 96%): mp 81-84° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.64 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.91 (dt,J=8.2, 0.8 Hz, 2H), 7.83-7.74 (m, 2H), 7.33 (dd, J=8.0, 0.7 Hz, 2H),4.14 (q, J=7.1 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 2.67 (dd, J=8.3, 7.2 Hz,2H), 1.35 (td, J=7.1, 0.6 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.50;ESIMS m/z 390 ([M+H]⁺).

Preparation of ethyl3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CB15)

The title compound was prepared from (E)-ethyl3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(CB12) and isolated as a gray solid (1.14 g, 98%): mp 109-111° C.; ¹HNMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.95 (ddd,J=7.8, 2.0, 0.7 Hz, 1H), 7.83-7.77 (m, 2H), 7.38 (dq, J=7.9, 1.0 Hz,2H), 7.26 (s, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.00 (dd, J=8.9, 7.0 Hz, 2H),2.69-2.55 (m, 2H), 2.41 (s, 3H), 1.26 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376MHz, CDCl₃) δ −58.03; ESIMS m/z 420 ([M+H]⁺).

Preparation of ethyl3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CB16)

The title compound was prepared from (E)-ethyl3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(CB13) using palladium hydroxide on carbon and ethanol as solvent;isolated as a tan solid (0.871 g, 67%, 85% pure): ¹H NMR (400 MHz,CDCl₃) δ 8.56 (s, 1H), 7.92-7.82 (m, 2H), 7.79 (d, J=9.0 Hz, 2H),7.43-7.36 (m, 2H), 7.32 (t, J=7.8 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.03(t, J=7.7 Hz, 2H), 2.67 (dd, J=8.2, 7.2 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H);¹⁹F NMR (376 MHz, CDCl₃) 5 (376 MHz, CDCl₃) δ −58.03, −117.98; ESIMS m/z423 ([M]⁺).

Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)butanoicacid (CB17)

The title compound was prepared from (E/Z)-ethyl2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)butanoate(CB14) and isolated as a brown solid (1.15 g, 28%): mp 149-150° C.; ¹HNMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.13-8.02 (m, 2H), 7.82-7.74 (m,2H), 7.38 (dq, J=8.9, 0.9 Hz, 2H), 7.35-7.28 (m, 2H), 3.04 (dd, J=13.7,8.3 Hz, 1H), 2.85 (dd, J=13.8, 6.6 Hz, 1H), 2.75-2.61 (m, 1H), 1.77-1.60(m, 2H), 1.00 (t, J=7.4 Hz, 3H) (OH not observed); ¹⁹F NMR (376 MHz,CDCl₃) 5 (376 MHz, CDCl₃) δ −58.03, −117.98; ESIMS m/z 406 ([M+H]⁺).

Example 31: Preparation of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (C32)

To ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate (C30) (0.975 g, 2.41 mmol) in methanol (60 mL) was addedsodium hydroxide (2 N, 12.0 mL, 24.1 mmol) and the solution was stirredat room temperature overnight. The methanol was concentrated undervacuum, and the residue was acidified with hydrogen chloride (2 N). Thewhite precipitate was vacuum filtered and dried to afford the titlecompound as a white solid (0.945 g, 99%): mp 145° C. (dec); ¹H NMR (400MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.04 (dd, J=21.4, 8.7 Hz, 4H), 7.62 (d,J=8.3 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.59 (t,J=7.6 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.98; ESIMS m/z 378([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 31.

Preparation of3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (C33)

The title compound was prepared from ethyl3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(C31) and isolated as a white solid (2.25 g, 100%): mp 142-144° C.; ¹HNMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.05 (dd, J=24.5, 8.6 Hz, 4H),7.62 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H),2.59 (t, J=7.6 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −74.86, −85.19,−86.92; ESIMS m/z 428 ([M+H]⁺).

Preparation of2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoicacid (CA10)

The title compound was prepared from ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoate(CA8) and isolated as a yellow oil (0.370 g, 33%): ¹H NMR (400 MHz,CDCl₃) δ 8.57 (d, J=4.0 Hz, 1H), 8.15-8.03 (m, 2H), 7.83-7.73 (m, 2H),7.40-7.27 (m, 4H), 3.18 (p, J=7.2 Hz, 1H), 2.76 (dq, J=8.3, 7.0 Hz, 1H),1.35-1.29 (m, 3H), 1.23 (d, J=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ−58.03; ESIMS m/z 406 ([M+H]⁺).

Preparation of3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CA11)

The title compound was prepared from ethyl3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CA9) and isolated as a white solid (2.85 g, 79%): mp 155-157° C.; ¹HNMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.52 (s, 1H), 8.26-8.12 (m, 2H),8.12-7.86 (m, 3H), 7.39 (d, J=8.2 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.59(t, J=7.6 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.79; ESIMS m/z 362([M+H]⁺).

Preparation of3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CB18)

The title compound was prepared from ethyl3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CB15) and isolated as a white solid (1.039 g, 96%): ¹H NMR (400 MHz,CD₃OD) δ 9.13 (s, 1H), 8.06-7.99 (m, 2H), 7.94 (d, J=1.8 Hz, 1H), 7.89(dd, J=7.8, 1.9 Hz, 1H), 7.54-7.46 (m, 2H), 7.30 (d, J=7.9 Hz, 1H), 2.99(t, J=7.9 Hz, 2H), 2.61 (dd, J=8.5, 7.2 Hz, 2H), 2.42 (s, 3H); ¹⁹F NMR(376 MHz, CD₃OD) δ −59.68; ESIMS m/z 391 ([M]⁺).

Preparation of3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CB19)

The crude title compound was prepared from ethyl3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CB16) and isolated as a white solid and used without furtherpurification: ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.01 (d, J=9.0 Hz,2H), 7.93-7.83 (m, 1H), 7.80 (dd, J=11.4, 1.6 Hz, 1H), 7.49 (d, J=8.6Hz, 2H), 7.41 (t, J=7.8 Hz, 1H), 3.00 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.6Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −55.72, −116.16; ESIMS m/z 395([M]⁺).

Example 32: Preparation of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (34) and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a)

To3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (C32) (0.70 g, 1.9 mmol) in anhydrous toluene (12 mL) was addedtriethylamine (0.26 mL, 1.9 mmol) and diphenyl phosphorazidate (0.40 mL,1.9 mmol). The reaction mixture was stirred at room temperature for 2hours, loaded directly onto a Celite® cartridge, and purified by flashcolumn chromatography using 0-100% ethyl acetate/hexanes as eluentaffording the title compound as a white solid (0.37 g, 50%). ¹H NMR isconsistent with a mixture of the acyl azide (34) and the rearrangedisocyanate (34a): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (two singlets,total=1H), 8.20-8.07 (m, 2H), 7.80 (m, 2H), 7.44-7.27 (m, 4H), 3.59 (t,J=6.9 Hz, 1H), 3.00 (t, J=7.2 Hz, 2H), 2.72 (d, J=7.2 Hz, 1H); ¹⁹F NMR(376 MHz, CDCl₃) δ −58.03; ESIMS m/z 403 ([M+H]⁺) (acyl azide).

The following compounds were prepared in accordance to the procedure inExample 32.

Preparation of3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C35)

The title compound was prepared from3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (C33) and was isolated as a white solid (0.416 g, 57%): mp 68° C.(dec.): ¹H NMR is consistent with a mixture of the acyl azide and therearranged isocyanate: ¹H NMR (400 MHz, CDCl₃) δ 8.64-8.53 (m, 1H),8.23-8.06 (m, 2H), 7.85-7.75 (m, 2H), 7.39 (m, 2H), 7.36-7.28 (m, 2H),3.59 (t, J=6.8 Hz, 1H), 3.00 (t, J=7.3 Hz, 2H), 2.70 (d, J=7.2 Hz, 1H);¹⁹F NMR (376 MHz, CDCl₃) δ −85.90, −87.85; ESIMS m/z 453 ([M+H]⁺).

Preparation of2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoylazide/3-(4-(3-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C35a)

The title compounds were prepared from2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoicacid (CA10) and isolated as a clear oil (3:1 azide:isocyanate, 0.246 g,67%): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.20-8.10 (m, 2H),7.83-7.73 (m, 2H), 7.42-7.28 (m, 4H), 3.77 (m, 1H), 2.86 (m, 1H), 1.39(two d, J=7.0 Hz, 3H), 1.25 (two d, J=6.5 Hz, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.03; ESIMS m/z 431 ([M+H]⁺).

Preparation of3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide/3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole(C35b)

The title compounds were prepared from3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CA11) and isolated as a clear oil (mixture azide:isocyanate, 0.595g, 57%): ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=2.8 Hz, 1H), 8.21-8.10 (m,2H), 7.91 (m, 2H), 7.80 (m, 2H), 7.38-7.29 (m, 2H), 3.59 (t, J=6.9 Hz,1H), 3.00 (t, J=7.2 Hz, 2H), 2.72 (d, J=7.2 Hz, 1H); ¹⁹F NMR (376 MHz,CDCl₃) δ −62.49.

Preparation of3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB20)

The title compound was prepared from3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CB18) using acetonitrile as co-solvent and was isolated as a whitesolid (0.636 g, 57%): ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.00 (d,J=1.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.84-7.75 (m, 2H), 7.39 (ddt, J=7.9,2.0, 1.0 Hz, 2H), 7.24 (d, J=7.9 Hz, 1H), 3.06-2.90 (m, 2H), 2.75-2.59(m, 2H), 2.41 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.04; ESIMS m/z 389([M+H]—N₂ ⁺).

Preparation of3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB21)

The title compound was prepared from3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CB19) using acetonitrile as co-solvent and was isolated as a whitesolid (0.084 g, 29%): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 7.94-7.83(m, 2H), 7.83-7.75 (m, 2H), 7.39 (ddd, J=7.7, 1.9, 0.9 Hz, 2H),7.35-7.29 (m, 1H), 3.10-2.96 (m, 2H), 2.81-2.66 (m, 2H); ¹⁹F NMR (376MHz, CDCl₃) δ −58.03, −117.86.

Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)butanoylazide (CB22)

The title compound was prepared from2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)butanoicacid (CB17) and was isolated as a clear oil (0.512 g, 56%): ¹H NMR (400MHz, CDCl₃) δ 8.56 (s, 1H), 8.20-8.10 (m, 2H), 7.84-7.74 (m, 2H), 7.39(dt, J=8.0, 1.0 Hz, 2H), 7.36-7.29 (m, 2H), 3.68 (tdd, J=8.3, 5.3, 4.4Hz, 1H), 2.98-2.77 (m, 2H), 1.76-1.64 (m, 1H), 1.61-1.51 (m, 1H), 1.05(t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03, −117.86; ESIMS m/z431 ([M+H]⁺).

Example 32a: Preparation of3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C34a)

A 1 L three-neck round bottomed flask was equipped with mechanicstirrer, thermocouple, and condenser. Tetrahydrofuran (120 mL) wasadded. After it was cooled to −3° C., ethyl carbonochloridate (3.16 mL,33.2 mmol) and triethylamine (4.64 mL, 33.2 mmol) were added.3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (C32) (11.4 g, 30.2 mmol) was added in portions, keeping thereaction temperature below 0° C. The reaction mixture turned into whitesuspension quickly. LC-MS showed no starting material left after 1 hr. Asolution of sodium azide (2.16 g, 33.2 mmol) in water (44 mL) was addedslowly, keeping the reaction temperature below −2° C. The reactionmixture was stirred at −2° C. for 2 hours. Cold water (200 mL) was addedto the reaction mixture very slowly while stirring at 0° C. It wasstirred at 0° C. for 30 minutes after the addition. The white solid thatformed was filtered while it was cold. The solid was dried in vacuumunder a stream of nitrogen at room temperature for 48 hours to affordthe isocyanate as a tan solid (10.5 g, 86%): ¹H NMR (400 MHz, CDCl₃) δ8.56 (s, 1H), 8.20-8.11 (m, 2H), 7.85-7.76 (m, 2H), 7.47-7.30 (m, 4H),3.59 (t, J=6.9 Hz, 2H), 2.97 (t, J=6.9 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃)δ −58.02; ESIMS m/z 375.2 ([M+H]⁺).

Example 33: Preparation ofN-[2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F2)

3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) (0.19 g, 0.46 mmol) in acetonitrile (2.3 mL) was heated at80° C. for 2 hours. The reaction mixture was cooled and1-(2-isopropylphenyl)thiourea (0.11 g, 0.55 mmol) and cesium carbonate(0.20 g, 0.60 mmol) were added. The reaction was stirred at roomtemperature for 4 hours, and then quenched with water and extracted withethyl acetate (2×). The organic layers were dried over anhydrous sodiumsulfate, filtered, concentrated, and loaded onto a Celite® cartridgewith dichloromethane. Purification by flash column chromatography using0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluentafforded the title compound as a white powder (0.097 g, 36%).

The following compounds were prepared in accordance to the procedure inExample 33.

Preparation ofN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as awhite solid (0.158 g, 43%).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[2-[2-methyl-4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(FB1)

The title compound was prepared from3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB20) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated,without purification, as a white solid (0.180 g, 79%, 88% pure).

Preparation of1-[(2-isopropyl-5-methoxy-phenyl)carbamothioyl]-3-[2-[2-methyl-4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(FB2)

The title compound was prepared from3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB20) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) andisolated, without purification, as a yellow solid (0.165 g, 75%).

Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[2-[2-methyl-4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(FB5)

The title compound was prepared from3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB20) and 1-(2-ethylphenyl)thiourea and isolated, withoutpurification, as a yellow solid (0.144 g, 83%).

Example 34: Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F1), Method A

ToN-[2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F2) (0.030 g, 0.053 mmol) and sodium acetate (0.016 g, 0.20mmol) in ethanol (0.5 mL) was added methyl 2-bromoacetate (0.01 mL, 0.10mmol) and the solution was heated at 65° C. for 1.5 hours. The reactionwas cooled and loaded directly onto a Celite® cartridge. Purification byflash column chromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes as eluent afforded the title compound as a clearoil (0.016 g, 49%).

Example 35: Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F1), Method B

3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) (0.24 g, 0.59 mmol) in acetonitrile (2.9 mL) was heated at80° C. for 2 hours. The reaction was cooled and cesium carbonate (0.29g, 0.88 mmol) and 1-(2-isopropylphenyl)thiourea (0.14 g, 0.70 mmol) wereadded. The reaction was stirred at room temperature overnight. LC/MSshowed formation of the thiobiuret was complete. The reaction mixturewas diluted with ethanol (2.9 mL) and sodium acetate (0.19 g, 2.4 mmol)and methyl 2-bromoacetate (0.12 mL, 1.2 mmol) were added. The solutionwas heated at 65° C. for 2 hours. The reaction was diluted with ethylacetate and washed with water. The organic layer was dried overanhydrous sodium sulfate, filtered, concentrated, and loaded onto aCelite® cartridge with dichloromethane. Purification by flash columnchromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent afforded the title compound as a tanoil (0.22 g, 62%).

The following compounds were prepared in accordance to the procedure inExamples 34 or 35.

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5)

The title compound was prepared as described in Example 34 usingN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated asa pale pink solid (0.114 g, 29%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F6)

The title compound was prepared as described in Example 35 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) andisolated as an orange solid (0.075 g, 35%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F9)

The title compound was prepared as described in Example 35 using1-(2-isopropyl-5-methylphenyl)thiourea and3-(4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-propanoylazide (C35) and isolated as a brown gum (0.146 g, 43%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-2-yl)urea(P66, P353)

The title compound was prepared as described in Example 35 using1-(2-isopropyl-5-methylphenyl)thiourea and2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoylazide/3-(4-(3-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C35a) and isolated as an off-white powder (0.146 g, 39%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P52)

The title compound was prepared as described in Example 35 using3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide/3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole(C35b) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as a tanglassy foam (0.132 g, 46%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P53)

The title compound was prepared as described in Example 35 using3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide/3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole(C35b) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) and isolatedas a brown foam (0.040 g, 30%).

Preparation of(Z)-1-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)urea(FB8)

The title compound was prepared as described in Example 35 using3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (CB21) and 1-(2-isopropyl-5-methylphenyl)thiourea at a temperatureof 60° C. and followed by reverse phase chromatography; isolated as anorange oil (0.028 g, 13%).

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB50)

The title compound was prepared as described in Example 35 using3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide/3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole(C35b) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) at atemperature of 60° C.; isolated as a clear oil (0.019 g, 12%).

Example 35a: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5)

To a 250 mL round bottomed flask was added acetonitrile (100 mL).3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(34a) (11.0 g, 29.4 mmol) was added in one portion.1-(2-Isopropyl-5-methylphenyl)thiourea (6.73 g, 32.3 mmol) and cesiumcarbonate (9.57 g, 29.4 mmol) were added to the above solution. Thereaction mixture was stirred at room temperature under nitrogenovernight. Ethanol (100 mL) was added to the mixture. Methyl2-bromoacetate (8.99 g, 58.8 mmol) and sodium acetate (9.64 g, 118 mmol)were then added. The reaction mixture was stirred at 60° C. for 2 hours,forming an orange suspension. The reaction mixture was cooled andfiltered through a filter paper, and the solids were washed with ethylacetate (2×100 mL). The orange filtrate was concentrated. The solidresidue was purified by flash column chromatography using 10-20%dichloromethane/B, where B=1:1 ethyl acetate/acetone, as eluent toafford the title compound as a slightly orange foam (8.60 g, 45%).

The following compounds were prepared in accordance to the procedure inExample 35a.

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P26)

The title compound was prepared from1-(2-isopropyl-4-methylphenyl)thiourea and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a brown oil (0.121 g, 47%).

Preparation of(Z)-1-(3-(2-isopropyl-3-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P27)

The title compound was prepared from1-(2-isopropyl-3-methylphenyl)thiourea and3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a yellow oil (0.075 g, 31%).

Preparation of(Z)-1-(3-(5-methyl-2-propylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P29)

The title compound was prepared from 1-(5-methyl-2-propylphenyl)thiourea(CA38) and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a pale pink solid (0.113 g, 43%).

Preparation of(Z)-1-(3-(2-(tert-butyl)phenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P30)

The title compound was prepared from 1-(2-(tert-butyl)phenyl)thioureaand3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a pink solid (0.076 g, 31%).

Preparation of(Z)-1-(3-(2-ethyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P31)

The title compound was prepared from 1-(2-ethyl-4-methylphenyl)thiourea(CA42) and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a pink solid (0.114 g, 47%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P44)

The title compound was prepared as described in Example 35a using1-(4-methoxy-2-methylphenyl)thiourea and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a yellow solid (0.120 g, 49%).

Preparation of(Z)-1-(3-(2-ethyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (P49)

The title compound was prepared from 1-(2-ethyl-5-methylphenyl)thiourea(CA41) and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a pink solid (0.099 g, 43%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P50)

The title compound was prepared from 1-(2-ethyl-6-methylphenyl)thiourea(CA39) and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as an off-white solid (0.076 g, 33%).

Preparation of(Z)-1-(3-(4-methoxy-2,6-dimethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P47)

The title compound was prepared from1-(4-methoxy-2,6-dimethylphenyl)thiourea and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a yellow oil (0.055 g, 23%).

Preparation of(Z)-1-(3-(3-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P51)

The title compound was prepared from 1-(3-isopropylphenyl)thiourea and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a dark brown oil (0.094 g, 37%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P28)

The title compound was prepared from1-(4-fluoro-2-isopropylphenyl)thiourea and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a brown foam (0.151 g, 37%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-5-methyl-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P57)

The title compound was prepared from1-(2-isopropyl-5-methylphenyl)thiourea,3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a), and methyl 2-brompropanoate and isolated as a clear sticky oil(0.192 g, 49%).

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB40)

The title compound was prepared from1-(5-chloro-2-isopropylphenyl)thiourea (CB32) and3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and isolated as a brown glassy foam (0.173 g, 48%).

Example 36: Preparation of (E)-ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C36)

4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(7.56 g, 22.7 mmol) and ethyl 2-(triphenylphosphoranylidene)propanoate(9.87 g, 27.2 mmol) in anhydrous toluene (30 mL) was heated at 110° C.for 16 hours. Additional ethyl 2-(triphenylphosphoranylidene)propanoate(2.40 g, 6.06 mmol) was then added, and the reaction was heated at 110°C. for 4 hours. The reaction was cooled, concentrated under vacuum, andloaded onto silica gel. Purification by flash column chromatographyusing 0-100% ethyl acetate/hexanes as eluent followed by reverse-phaseflash column chromatography using 0-100% acetonitrile/water as eluentafforded the title compound as a white solid (5.92 g, 62%): mp126-127.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.27-8.17 (m,2H), 7.84-7.78 (m, 2H), 7.73 (s, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.40 (d,J=8.3 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 2.17 (d, J=1.5 Hz, 3H), 1.37 (t,J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 418([M+H]⁺).

Example 37: Preparation of ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(C37)

A flask containing (E)-ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C36) (0.96 g, 2.3 mmol) and palladium on carbon (10 wt %, 0.24 g, 0.23mmol) in ethyl acetate (10 mL) was evacuated under vacuum, filled withnitrogen, evacuated under vacuum, and then placed under hydrogen byballoon (˜1 atm). After stirring at room temperature for 20 hours, thereaction was filtered through a pad of Celite® and concentrated toafford the title compound as a white solid (1.0 g, 100%): mp 73-75° C.;¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.14-8.07 (m, 2H), 7.86-7.76 (m,2H), 7.39 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 4.10 (q, J=7.1 Hz,2H), 3.22-2.99 (m, 1H), 2.75 (dq, J=13.3, 7.5 Hz, 2H), 1.24-1.15 (m,6H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 420 ([M+H]⁺).

Example 38: Preparation of2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (C38)

To ethyl2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(C37) (0.986 g, 2.35 mmol) in methanol (7.8 mL) was added sodiumhydroxide (2 N, 5.9 mL, 11.8 mmol) and the solution was stirred at roomtemperature for 4 hours. The reaction was acidified with hydrogenchloride (2 N), and the white precipitate was vacuum-filtered to affordthe title compound as a white solid (0.865 g, 93%): mp 142-144° C.; ¹HNMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 9.39 (s, 1H), 8.14-7.95 (m, 4H),7.71-7.55 (m, 2H), 7.42-7.27 (m, 2H), 3.04-2.89 (m, 1H), 2.75-2.62 (m,2H), 1.07 (d, J=6.2 Hz, 3H). ¹⁹F NMR (376 MHz, acetone-D₆) δ −58.03;ESIMS m/z 392 ([M+H]⁺).

Example 39: Preparation of3-(4-(2-isocyanatopropyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C39)

To2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-propanoicacid (0.84 g, 2.2 mmol) in toluene (21.6 mL) was added triethylamine(0.33 mL, 2.4 mmol) and diphenyl phosphorazidate (0.47 mL, 2.2 mmol) andthe solution was stirred at room temperature for 2 hours. The reactionwas diluted with ethyl acetate and water and the layers separated. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was loaded onto a Celite® cartridge andpurified by flash column chromatography using 0-100% ethyl acetate/B,where B=1:1 dichloromethane/hexanes, as eluent to afford the titlecompound as a white solid (0.53 g, 58%): ¹H NMR (400 MHz, CDCl₃) δ 8.56(s, 1H), 8.21-8.11 (m, 2H), 7.88-7.77 (m, 2H), 7.39 (d, J=8.3 Hz, 2H),7.32 (d, J=8.4 Hz, 2H), 3.94-3.80 (m, 1H), 2.87 (d, J=6.8 Hz, 2H), 1.35(d, J=6.5 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 389([M+H]⁺).

Example 40: Preparation ofN-[2-(propan-2-yl)phenyl]-N′-[1-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)propan-2-yl]dicarbonimidothioicdiamide (F4)

3-(4-(2-Isocyanatopropyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C39) (0.17 g, 0.41 mmol) in acetonitrile (2.1 mL) was heated at 80° C.for 2 hours to ensure complete conversion to the isocyanate. Thereaction was cooled and 1-(2-isopropylphenyl)thiourea (0.83 g, 0.43mmol) and cesium carbonate (0.17 g, 0.53 mmol) were added and stirred atroom temperature overnight. The reaction was diluted with ethyl acetateand washed with water. The aqueous layer was extracted with ethylacetate, and the combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated to afford the title compoundas a white solid (0.25 g, 95%).

Example 41: Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(F7)

ToN-[2-(propan-2-yl)phenyl]-N′-[1-(4-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}phenyl)propan-2-yl]dicarbonimidothioicdiamide (F4) (0.20 g, 0.34 mmol) and sodium acetate (0.056 g, 0.68 mmol)in ethanol (2.3 mL) was added methyl 2-bromoacetate (0.05 mL, 0.51mmol), and the reaction was heated at 65° C. for 2 hours. The reactionwas cooled and diluted with water and extracted with ethyl acetate (2×).The organic layers were dried over anhydrous sodium sulfate, filtered,and concentrated. The crude material was loaded onto a silica gelcartridge with dichloromethane and purified by flash columnchromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent to afford the title compound as awhite solid (0.070 g, 33%).

Example 42: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(F8)

3-(4-(2-Isocyanatopropyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C39) (0.17 g, 0.41 mmol) in acetonitrile (2 mL) was heated at 80° C.for 2 hours to ensure complete conversion to the isocyanate. Thereaction was cooled and 1-(2-isopropyl-5-methylphenyl)thiourea (0.095 g,0.46 mmol) and cesium carbonate (0.20 g, 0.60 mmol) were added. Thereaction was stirred at room temperature for 3 days. The reaction wasdiluted with ethanol (2.5 mL) and sodium acetate (0.064 g, 0.78 mmol)and methyl 2-bromoacetate (0.05 mL, 0.53 mmol) were added. The reactionwas heated at 65° C. for 2.5 hours. The reaction mixture was dilutedwith ethyl acetate and washed with water. The aqueous layer wasextracted an additional time with ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was loaded onto a Celite® cartridge andpurified by flash column chromatography using 0-100% ethyl acetate/B,where B=1:1 dichloromethane/hexanes, as eluent to afford the titlecompound as an off-white solid (0.054 g, 20%).

The following compounds were prepared in accordance to the procedure inExample 42.

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(P33)

The title compound was prepared from2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C39) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as abrown solid (0.183 g, 60%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(P42)

The title compound was prepared from2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C39) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) and isolatedas an off-white solid (0.117 g, 39%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(P45)

The title compound was prepared from2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C39) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as abrown solid (0.224 g, 65%).

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(FB42)

The title compound was prepared from2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C39) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) andisolated as a brown oil (0.110 g, 46%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-2-yl)urea(FB43) 12412827

The title compound was prepared from2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)butanoylazide (CB22) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated asa peach glassy foam (0.122 g, 53%).

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-2-yl)urea(FB44)

The title compound was prepared from2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)butanoylazide (CB22) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) andisolated as a tan glassy foam (0.132 g, 60%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(FB47)

The title compound was prepared from2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C39) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) andisolated as a brown oil (0.146 g, 42%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(FB48)

The title compound was prepared from2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C39) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as abrown oil (0.130 g, 47%).

Example 43: Preparation of ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoate(C40)

A flask containing (E)-ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate(C26) (1.80 g, 4.31 mmol) and palladium on carbon (10 wt %, 0.46 g, 0.43mmol) in ethyl acetate (14.5 mL) was evacuated and backfilled withnitrogen, and then evacuated and placed under hydrogen by balloon (˜1atm). The reaction was stirred at room temperature overnight, and thenfiltered through Celite® and concentrated to afford the title compoundas a tan liquid (1.79 g, 98%): ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H),8.17-8.07 (m, 2H), 7.87-7.75 (m, 2H), 7.38 (d, J=9.1 Hz, 2H), 7.36-7.31(m, 2H), 4.08 (qd, J=7.1, 0.8 Hz, 2H), 3.35 (dd, J=14.6, 7.2 Hz, 1H),2.62 (qd, J=15.1, 7.6 Hz, 2H), 1.34 (d, J=7.0 Hz, 3H), 1.19 (t, J=7.1Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 420 ([M+H]⁺).

Example 44: Preparation of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoicacid (C41)

To ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoate(C40) (1.78 g, 4.24 mmol) in methanol (14 mL) was added sodium hydroxide(2 N, 12.7 mL, 25.4 mmol) and stirred at room temperature for 4 hours.The reaction acidified with hydrogen chloride (2 N), and the methanolwas concentrated off under vacuum. The aqueous solution was extractedwith ethyl acetate (3×). The organic layers were dried over anhydroussodium sulfate, filtered, and concentrated to afford the title compoundas a clear gum (0.470 g, 28%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H),8.11-8.05 (m, 2H), 8.02 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.41(d, J=8.3 Hz, 2H), 3.21 (dd, J=14.4, 7.1 Hz, 1H), 2.56 (d, J=7.4 Hz,2H), 1.26 (d, J=7.0 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMSm/z 392 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 44.

Preparation of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoicacid (CA12)

The title compound was prepared from ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoate(CA48) and isolated as a white solid (0.927 g, 36%): ¹H NMR (400 MHz,DMSO-d₆) δ 12.05 (s, 1H), 9.39 (s, 1H), 8.17-7.94 (m, 4H), 7.73-7.51 (m,2H), 7.46-7.25 (m, 2H), 2.96 (ddd, J=14.7, 8.7, 6.0 Hz, 1H), 2.64 (dd,J=15.5, 6.6 Hz, 1H), 2.55-2.49 (m, 1H), 1.79-1.49 (m, 2H), 0.74 (t,J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.99; ESIMS m/z 406([M+H]⁺).

Example 45: Preparation of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoylazide (C42)

To3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoicacid (C41) (1.77 g, 4.52 mmol) in toluene (18 mL) was addedtriethylamine (0.82 mL, 5.88 mol) and diphenyl phosphorazidate (1.05 mL,4.98 mmol) and the solution was stirred at room temperature for 3 hours.The reaction was diluted with ethyl acetate and washed with water. Theaqueous layer was extracted with ethyl acetate. The organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude material was loaded onto a Celite® cartridge and purified by flashcolumn chromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent to afford the title compound as aclear oil (0.223 g, 12% yield): ¹H NMR is consistent with a mixture ofcarbonyl azide and isocyanate. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H),8.28-8.03 (m, 2H), 7.88-7.66 (m, 2H), 7.48-7.30 (m, 4H), 3.60-3.40 (m,2H), 3.08 (q, J=6.9 Hz, 1H), 2.81-2.49 (m, 1H), 1.37 (dd, J=10.4, 7.0Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 417 ([M+H]⁺)

The following compounds were prepared in accordance to the procedure inExample 45.

Preparation of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoylazide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C42a)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoicacid (CA12) to furnish a mixture of azide and isocyanate, 0.723 g, 72%):¹H NMR (400 MHz, CDCl₃) δ 8.56 (two s, 1H), 8.20-8.15 (m, 2H), 7.85-7.74(m, 2H), 7.39 (dt, J=9.0, 1.0 Hz, 2H), 7.34-7.29 (m, 2H), 3.62-3.38 (m,2H), 2.77-2.59 (m, 1H), 1.93-1.59 (m, 2H), 0.94-0.83 (m, 3H).

Example 46: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(F10)

3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoylazide (C42) (0.22 g, 0.52 mmol) in acetonitrile (2.6 mL) was heated at80° C. for 2 hours. The reaction was cooled and1-(2-isopropyl-5-methylphenyl)thiourea (0.12 g, 0.57 mmol) and cesiumcarbonate (0.20 g, 0.61 mmol) were added. The reaction was stirred atroom temperature for 18 hours. Sodium acetate (0.093 g, 1.1 mmol),methyl 2-bromoacetate (0.07 mL, 0.78 mmol) and ethanol (2.6 mL) wereadded, and the reaction mixture was heated at 65° C. for 3 hours. Thereaction was cooled, diluted with ethyl acetate, and washed with water.The aqueous layer was extracted once more with ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated. The crude material was loaded onto a Celite®cartridge and purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent to afford thetitle compound as an orange solid (0.12 g, 35%).

The following compounds were prepared in accordance to the procedure inExample 46.

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P364)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoylazide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C42a) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as a pinksolid (0.110 g, 43%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P683)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoylazide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C42a) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) and isolatedas a brown foam (0.091 g, 47%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P209)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoylazide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C42a) and 1-(2-isopropylphenyl)thiourea and isolated as a brown foam(0.041 g, 30%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P1163)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoylazide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C42a) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as abrown foam (0.072 g, 30%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P679)

The title compound was prepared as described in Example 46 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoylazide (C42) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) andisolated as a brown solid (0.118 g, 54%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P205)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoylazide (C42) and 1-(2-isopropylphenyl)thiourea and isolated as a brownsolid (0.105 g, 43%).

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(FB49)

The title compound was prepared from3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoylazide (C42) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) andisolated as a brown oil (0.055 g, 22%).

Example 47: Preparation of1-(4-(trifluoromethoxy)phenyl)-3-(4-vinylphenyl)-1H-1,2,4-triazole (C43)

Methyltriphenylphosphonium bromide (32.2 g, 90.0 mmol) and1,8-diazabicycloundec-7-ene (14.9 mL, 99.0 mmol) were dissolved intetrahydrofuran (260 mL) and refluxed for 30 minutes.4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(15.0 g, 45.0 mmol) was added, and the reaction was heated at 65° C. for5 hours. The solution was cooled and stirred at room temperatureovernight. The reaction mixture was poured into water and extracted withhexanes. The organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated. The crude compound was purified by flashcolumn chromatography using 0-70% ethyl acetate/hexanes as eluent toafford the title compound as a white solid (10.4 g, 67%): ¹H NMR (400MHz, CDCl₃) δ 8.57 (s, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.80 (d, J=9.0 Hz,2H), 7.58-7.47 (m, 2H), 7.39 (d, J=9.1 Hz, 2H), 6.77 (dd, J=17.6, 10.9Hz, 1H), 5.84 (dd, J=17.6, 0.8 Hz, 1H), 5.32 (dd, J=10.9, 0.8 Hz, 1H);¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 332 ([M+H]⁺).

Example 48: Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanol(C44)

To 1-(4-(trifluoromethoxy)phenyl)-3-(4-vinylphenyl)-1H-1,2,4-triazole(C43) (2.0 g, 6.0 mmol) in tetrahydrofuran (50 mL) was added9-borabicyclo(3.3.1)nonane (24 mL, 12.1 mmol), and the reaction wasstirred at room temperature for 4.5 hours. Sodium hydroxide (3 N, 4.0mL, 12.0 mmol) was added, followed by hydrogen peroxide (30% wt, 1.5 mL,15.1 mmol). The light green solution was stirred at room temperatureovernight. The reaction mixture was diluted with water and extractedwith ethyl acetate. The organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated to give a light green oil. The crudecompound was purified by flash column chromatography using 0-50% ethylacetate/hexanes as eluent to afford the title compound as a white solid(1.5 g, 69%): mp 85-98° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H),8.06 (d, J=9.0 Hz, 2H), 8.01 (d, J=8.1 Hz, 2H), 7.61 (dd, J=9.2, 1.0 Hz,2H), 7.41-7.30 (m, 2H), 4.69 (t, J=5.2 Hz, 1H), 3.65 (td, J=7.0, 5.1 Hz,2H), 2.79 (t, J=6.9 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 162.18,147.08, 143.70, 141.45, 135.72, 129.39, 128.23, 127.93, 125.96, 122.57,121.10, 61.90, 61.90; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.98; ESIMS m/z 349([M+H]⁺).

Example 49: Preparation of ethyl2,3-difluoro-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(C45)

Step 1.

Sodium hydride (60% oil immersion, 0.48 g, 12 mmol) was added to a dry,oven-dried round bottomed flask and placed under nitrogen. Diethyl ether(9 mL) was added, followed by absolute ethanol (0.05 mL), and thereaction was cooled in an ice bath. Ethyl 2-fluoroacetate (0.87 mL, 9.0mmol) was added dropwise. The reaction was stirred for 15 minutes in icebath (gas evolution ceased).4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(2.2 g, 6.5 mmol) was added in solid portions. The solution slowlyturned color to a golden yellow. The ice bath was removed after 1 hourand warmed to room temperature, stirring for an additional 2 hours untilthe reaction was quenched with saturated aqueous ammonium chloride,diluted with diethyl ether, and stirred at room temperature for 3 days.The biphasic solution was diluted with brine and extracted with ethylacetate (2×). The organic layers were dried organic over anhydroussodium sulfate, filtered, and concentrated to give an orange liquid. Thecrude material was purified by reverse-phase flash column chromatographyusing 0-100% acetonitrile/water as eluent to afford the intermediateethyl2-fluoro-3-hydroxy-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoateas a crude compound (0.11 g).

Step 2.

To the crude ethyl2-fluoro-3-hydroxy-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(0.11 g, 0.26 mmol) in dichloromethane (1.7 mL) at 0° C. was addedDeoxo-Fluor® (0.05 mL, 0.28 mmol) and stirred for 30 minutes. Thereaction mixture was loaded onto a Celite® cartridge and purified byflash column chromatography using 0-60% ethyl acetate/hexanes as eluentto afford the title compound as a yellow oil (0.054 g, 47%): ¹H NMR (400MHz, CDCl₃) δ 8.58 (d, J=1.9 Hz, 1H), 8.32-8.14 (m, 2H), 7.87-7.73 (m,2H), 7.50 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.11-5.76 (m, 1H),5.52-4.90 (m, 1H), 4.27 (dqd, J=23.6, 7.1, 2.1 Hz, 2H), 1.27 (dt,J=19.4, 7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.04, −187.64,−187.68, −192.41, −192.44, −202.56, −202.60, −204.97, −205.00; ESIMS m/z442 ([M+H]⁺).

Example 50: Preparation of (Z)-ethyl2-cyano-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C46)

To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(3.0 g, 9.0 mmol) in ethanol (11.5 mL) was added ethyl 2-cyanoacetate(0.95 mL, 8.9 mmol) and pyrrolidine (0.97 mL, 12 mmol). A yellowprecipitate formed immediately and additional ethanol (10 mL) was added.The reaction was stirred at room temperature for 18 hours and thenconcentrated onto Celite®. Purification by flash column chromatographyusing 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes aseluent afforded the title compound as a white solid (2.1 g, 50%): ¹H NMR(400 MHz, CDCl₃) δ 8.61 (s, 1H), 8.36-8.31 (m, 2H), 8.29 (s, 1H), 8.12(d, J=8.4 Hz, 2H), 7.85-7.79 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.41 (q,J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ162.46, 162.24, 154.18, 141.89, 135.36, 134.76, 132.41, 131.53, 127.22,122.47, 121.33, 115.51, 103.28, 62.82, 14.19; ESIMS m/z 429 ([M+H]⁺).

Example 51: Preparation of(Z)-2-cyano-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylicacid (C47)

To (Z)-ethyl2-cyano-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate(C46) (2.5 g, 5.8 mmol) in tetrahydrofuran/methanol/water (3:2:1, 42 mL)was added lithium hydroxide (2.5 mL, 7.5 mmol) and stirred at roomtemperature for 18 hours. The reaction mixture was concentrated undervacuum, cooled in an ice bath, and acidified with hydrogen chloride (2N). The precipitate was filtered and washed with cold water to affordthe title compound as a brown solid (2.2 g, 82%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.49 (s, 1H), 8.39 (s, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.18 (d,J=8.5 Hz, 2H), 8.13-8.08 (m, 2H), 7.64 (d, J=8.4 Hz, 2H); ESIMS m/z 401([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 51.

Preparation of3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CA13)

The title compound was prepared from methyl3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate(CA1) and isolated as a tan solid (9.09 g, 94%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.41 (s, 1H), 8.13-8.04 (m, 2H), 7.98 (t, J=1.7 Hz, 1H), 7.94(dt, J=7.7, 1.4 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.43 (t, J=7.6 Hz, 1H),7.35 (dt, J=7.7, 1.4 Hz, 1H), 2.93 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz,2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.99; ESIMS m/z 378 ([M+H]⁺), 376([M−H]⁻).

Preparation of2-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (CB23)

The title compound was prepared from methyl2-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate(CB11) and isolated as a light brown solid (4.28 g, 88%): ¹H NMR (400MHz, DMSO-d₆) δ 12.40 (s, 1H), 9.42 (s, 1H), 8.13-8.06 (m, 2H),8.06-7.96 (m, 2H), 7.63 (dq, J=8.0, 1.0 Hz, 2H), 7.47 (td, J=7.6, 0.6Hz, 1H), 7.38 (dt, J=7.7, 1.5 Hz, 1H), 3.70 (s, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −56.97; ESIMS m/z 364 ([M+H]⁺), 362 ([M−H]⁻).

Example 52: Preparation of tert-butyl 4-bromophenethylcarbamate (C48)

To a stirring solution of 4-dimethylaminopyridine (0.19 g, 1.5 mmol) anddi-tert-butyl dicarbonate (2.6 g, 12 mmol) in dichloromethane (40 mL)was added 4-bromophenethylamine (1.6 mL, 10 mmol) and stirring wascontinued at room temperature for 48 hours. The reaction mixturedirectly adsorbed onto silica gel and purified by flash columnchromatography using 0-40% ethyl acetate/hexanes as eluent to afford thetitle compound as a white solid (0.68 g, 22%): mp 58-59° C.; ¹H NMR (400MHz, CDCl₃) δ 7.42 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 4.51 (s,1H), 3.43-3.27 (m, 2H), 2.75 (t, J=7.0 Hz, 2H), 1.43 (s, 9H); ¹³C NMR(101 MHz, CDCl₃) δ 155.79, 137.97, 131.62, 130.55, 120.25, 77.21, 41.58,35.65, 28.39; EIMS m/z 301 ([M]⁺).

Example 53: Preparation of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (C49)

A mixture of tert-butyl 4-bromophenethylcarbamate (C48) (0.68 g, 2.3mmol), bis(pinacolato)diborane (0.89 g, 3.5 mmol), potassium acetate(0.69 g, 7.0 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.10 g,0.14 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (0.075 g, 0.14mmol) in anhydrous dioxane (7 mL) was heated at 80° C. for 18 hours. Thereaction was cooled, diluted with ethyl acetate, and washed with water.The aqueous layer was extracted with ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated. The crude compound was adsorbed onto silica gel andpurified by flash column chromatography using 0-60% ethylacetate/hexanes as eluent to afford the title compound as a clear oil(0.86 g, 104%): ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J=7.9 Hz, 2H),7.23-7.17 (m, 2H), 4.51 (s, 1H), 3.46-3.28 (m, 2H), 2.81 (t, J=7.1 Hz,2H), 1.43 (s, 9H), 1.34 (s, 12H); ESIMS m/z 348 ([M+H]⁺).

Example 54: Preparation of tert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50)

A mixture of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C1) (0.55 g, 1.8 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl carbamate (C49)(0.63 g, 1.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.21 g,0.18 mmol), and sodium bicarbonate (0.33 g, 3.9 mmol) in dioxane/water(16 mL, 3:1) in a 20 mL vial was capped and heated at 140° C. for 30minutes in a Biotage Initiator® microwave reactor with externalIR-sensor temperature monitoring from the side of the vessel. Thereaction was diluted with ethyl acetate and washed with water. Theaqueous layers were extracted with ethyl acetate (2×), and the combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was loaded onto a Celite® cartridge andpurified by flash column chromatography using 0-100% ethyl acetate/B,where B=1:1 dichloromethane/hexanes, as eluent to provide the titlecompound as a white solid (0.48 g, 60%): mp 149-151° C.; ¹H NMR (400MHz, CDCl₃) δ 8.56 (s, 1H), 8.13 (d, J=8.1 Hz, 2H), 7.84-7.76 (m, 2H),7.42-7.35 (m, 2H), 7.31 (d, J=7.9 Hz, 2H), 4.55 (s, 1H), 3.51-3.34 (m,2H), 2.87 (t, J=7.0 Hz, 2H), 1.44 (s, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ−58.03; ESIMS m/z 449 ([M+H]⁺).

Example 55: Preparation of 3-(4-bromophenyl)-1H-1,2,4-triazole (C51)

4-Bromo benzamide (28.0 g, 0.140 mol) was suspended in1,1-dimethoxy-N,N-dimethylmethanamine (50 mL, 420 mmol) and the solutionwas stirred and heated to 90° C. for 2 hours. The solution was thencooled to ambient temperature and diethyl ether (150 mL) was added. Thesolution was cooled to 0° C. overnight and filtered to give(E)-4-bromo-N-((dimethylamino)methylene)benzamide as a colorless solid(25.6 g). This material was then dissolved in acetic acid (50 mL) andhydrazine (3.50 g, 110 mmol) was added slowly (exotherm) to the stirredsolution, which solidified. The mixture was heated to 90° C. and a stirbar was added. The solid slowly dissolved over 8 hours and was thencooled to ambient temperature and the solution was diluted with water(35 mL). The resulting white solid was filtered and dried in vacuo tofurnish the title compound as a colorless solid (19.8 g, 88%): ¹H NMR(400 MHz, DMSO-d₆) δ 13.91 (s, 1H), 8.51 (s, 1H), 8.01-7.93 (m, 2H),7.73-7.67 (m, 2H; ESIMS m/z 224, 226 ([M+H]⁺).

Example 56: Preparation of3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C52)

To a solution of 1-iodo-4-(trifluoromethoxy)benzene (15.0 g, 52.0 mmol)in dimethylformamide (90 mL) and water (10 mL) was added3-(4-bromophenyl)-1H-1,2,4-triazole (C51) (11.0 g, 49.0 mmol), cesiumcarbonate (34.0 g, 104 mmol), copper(I) iodide (2.80 g, 14.7 mmol), and8-hydroxyquinoline (2.20 g, 15.0 mmol), and the solution was heated at140° C. for 8 hours. The cooled solution was decanted from a layer ofsolid, diluted with a ammonium hydroxide (1 N, 100 mL) solution, andextracted with of diethyl ether (2×100 mL). The combined organic layerwas dried and concentrated, and the brown solid was eluted through ashort silica gel column using 20% ethyl acetate/hexanes as eluent togive the title compound as a light tan solid (9.50 g, 50%): mp 111-113°C.; ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.79(d, J=8.8 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H); ESIMSm/z 384 ([M+H]⁺).

Preparation of3-(4-bromophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C53)

The title compound was prepared as described in Example 56 using1-iodo-4-(trifluoromethyl)benzene to furnish the title compound as awhite solid (3.21 g, 64%): ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.06(d, J=8.6 Hz, 2H), 7.89 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.59(d, J=8.6 Hz, 2H); ESIMS m/z 368, 370 ([M+H]⁺).

Example 57: Preparation of tert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50)

To a solution of3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C52)(0.13 g, 0.32 mmol) in toluene (4 mL) and water (1 mL) was addedpotassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.082 g,0.33 mmol), palladium(II)acetate (0.027 g, 0.027 mmol), cesium carbonate(0.33 g, 1.0 mmol), anddicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (0.016 g,0.034 mmol), and the solution was stirred under nitrogen and heated to95° C. for 8 hours. The solution was then cooled and diluted withdiethyl ether (5 mL) and adsorbed onto a silica gel pre-column. Flashcolumn chromatography using 0-50% ethyl acetate/hexanes as eluentfurnished the title compound as a light tan solid (0.095 g, 63%): mp149-153° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.18-8.10 (m, 2H),7.84-7.77 (m, 2H), 7.43-7.35 (m, 2H), 7.31 (d, J=8.2 Hz, 2H), 4.58 (d,J=8.1 Hz, 1H), 3.49-3.34 (m, 1H), 2.87 (t, J=7.0 Hz, 1H), 1.44 (s, 9H);ESIMS m/z 449 ([M+H]⁺).

Example 58: Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(C55)

To a stirred and cooled (0° C.) solution of tert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50) (0.35 g, 0.77 mmol) in dichloromethane (2.6 mL) was addedtrifluoroacetic acid (0.060 mL, 0.78 mmol), and the solution was allowedto warm slowly to ambient temperature. After 18 hours, an additionalamount of trifluoroacetic acid (0.060 mL, 0.78 mmol) was added. After 24hours a third aliquot of trifluoroacetic acid (0.060 mL, 0.78 mmol) wasadded. After an additional 24 hours, the solution was concentrated togive the title compound as a tan solid (0.325 g, 88%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.41 (s, 1H), 8.08 (dd, J=8.8, 2.6 Hz, 4H), 7.87 (s, 2H),7.63 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 3.17-3.06 (m, 2H),2.99-2.89 (m, 2H); ESIMS m/z 349 ([M+H]+).

The following compounds were prepared in accordance to the procedure inExample 58.

Preparation ofN-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CB24)

The title compound was prepared from tert-butylmethyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB63), neutralized with aqueous sodium bicarbonate, and isolated as ayellow waxy solid with excess trifluoroacetic acid (5.73 g, 111%): ¹HNMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.77 (d,J=9.0 Hz, 2H), 7.37 (dd, J=9.0, 1.0 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H),3.23-3.12 (m, 2H), 3.05 (dd, J=9.4, 6.3 Hz, 2H), 2.67 (s, 3H), 1.29-1.22(m, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.04, −75.71; ESIMS m/z 363([M+H]⁺).

Preparation ofN-ethyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CB25)

The title compound was prepared from tert-butylethyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB64), neutralized with aqueous sodium bicarbonate, and isolated as anorange solid (0.167 g, 98%, 80% pure): ¹H NMR (400 MHz, CDCl₃) δ 8.54(s, 1H), 8.17-8.06 (m, 2H), 7.87-7.63 (m, 2H), 7.37 (dt, J=8.0, 1.0 Hz,2H), 7.34-7.28 (m, 2H), 3.21 (s, 2H), 3.14-2.97 (m, 4H), 1.84 (s, 1H),0.87 (ddd, J=12.0, 8.9, 6.6 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.04;ESIMS m/z 377 ([M+H]⁺).

Preparation ofN-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)prop-2-en-1-amine(CB26)

The title compound was prepared from tert-butylallyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB65), neutralized with aqueous sodium bicarbonate, and isolated as ayellow solid (0.124 g, 90%): mp 110-120° C.; ¹H NMR (400 MHz, CDCl₃) δ8.54 (s, 1H), 8.14-8.07 (m, 2H), 7.81-7.73 (m, 2H), 7.42-7.34 (m, 2H),7.34-7.28 (m, 2H), 5.92 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.43-5.22 (m,2H), 3.49 (dt, J=6.6, 1.2 Hz, 2H), 3.19-2.92 (m, 5H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.04; ESIMS m/z 389 ([M+H]⁺).

Preparation ofN-(cyclopropylmethyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CB27)

The title compound was prepared fromtert-butyl(cyclopropylmethyl)(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB66), neutralized with aqueous sodium bicarbonate, and isolated as awhite solid (0.125 g, 100%): mp 162-166° C.; ¹H NMR (400 MHz, CDCl₃) δ8.54 (s, 1H), 8.15-8.09 (m, 2H), 7.81-7.75 (m, 2H), 7.38 (dq, J=8.9, 0.9Hz, 2H), 7.34-7.29 (m, 2H), 3.22 (dd, J=10.2, 6.0 Hz, 2H), 3.09 (dd,J=10.0, 6.1 Hz, 2H), 2.84 (d, J=7.3 Hz, 2H), 1.11 (ddd, J=12.7, 8.1, 4.8Hz, 1H), 0.86 (dd, J=12.8, 5.8 Hz, 1H), 0.69-0.58 (m, 2H), 0.37-0.29 (m,2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 403 ([M+H]⁺).

Example 58a: Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CA51)

To a stirred and cooled (0° C.) solution of tert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50) (0.10 g, 0.22 mmol) in dichloromethane (1.6 mL) was addedtrifluoroacetic acid (0.19 mL, 0.25 mmol), and the solution was allowedto warm slowly to ambient temperature and stirred overnight. Thereaction mixture was concentrated, taken up in hexanes, and concentrateduntil a solid was obtained. The solid was dissolved in dichloromethaneand washed with saturated sodium bicarbonate. The aqueous layer wasextracted with dichloromethane (2×). The combined organic layers werewashed with saturated sodium bicarbonate. The organic layers were driedover magnesium sulfate, filtered, and concentrated to give the titlecompound as a white solid (0.075 g, 97%): ¹H NMR (400 MHz, CDCl₃) δ 8.56(s, 1H), 8.18-8.07 (m, 2H), 7.83-7.74 (m, 2H), 7.41-7.29 (m, 4H), 3.02(t, J=6.8 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 1.45-1.29 (m, 2H); ¹⁹F NMR(376 MHz, CDCl₃) δ −58.04.

Example 59: Preparation of2-(3-(4-bromophenyl)propyl)isoindoline-1,3-dione (C56)

To 3-(4-bromophenyl)propan-1-ol (4.70 g, 21.9 mmol),isoindoline-1,3-dione (3.54 g, 24.0 mmol) and triphenylphosphine (6.88g, 26.2 mmol) in a 500 mL round bottomed flask equipped with a stir bar,nitrogen, and addition funnel, and cooled in an ice water bath was addeddiisopropyl azodicarboxylate (5.10 mL, 26.2 mmol). The reaction wasallowed to warm to room temperature over the weekend. The reactionmixture was adsorbed onto Celite®. Purification by flash columnchromatography using 5-20% ethyl acetate/hexanes as eluent provided asolid which was dried overnight at 50° C. in vacuo to afford the titlecompound as a white solid (6.51 g, 87%): mp 88-90° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.86-7.79 (m, 2H), 7.71 (dd, J=5.5, 3.0 Hz, 2H), 7.38-7.32 (m,2H), 7.11-7.04 (m, 2H), 3.73 (t, J=7.1 Hz, 2H), 2.68-2.59 (m, 2H),2.07-1.96 (m, 2H); ESIMS m/z 346 [(M+2)⁺].

The following compounds were prepared in accordance to the procedure inExample 59.

Preparation of 2-(3-bromophenethyl)isoindoline-1,3-dione (C57)

The title compound was prepared from 2-(3-bromophenyl)ethanol to affordthe title compound as a white solid (3.92 g, 81%): mp 100-104° C.; ¹HNMR (400 MHz, CDCl₃) δ 7.88-7.81 (m, 2H), 7.76-7.69 (m, 2H), 7.43-7.39(m, 1H), 7.35 (dt, J=7.4, 1.8 Hz, 1H), 7.22-7.13 (m, 2H), 3.94-3.87 (m,2H), 2.99-2.92 (m, 2H); ESIMS m/z 332 ([M+2]⁺).

Preparation of 2-(4-(3-bromophenyl)butyl)isoindoline-1,3-dione (C57a)

The title compound was prepared from 4-(3-bromophenyl)butan-1-ol (C86)to afford the title compound as a white solid (7.68 g, 62%): ¹H NMR (400MHz, DMSO-d₆) δ 7.91-7.78 (m, 4H), 7.40 (t, J=1.9 Hz, 1H), 7.35 (dt,J=7.2, 2.0 Hz, 1H), 7.28-7.15 (m, 2H), 3.59 (t, J=6.5 Hz, 2H), 2.59 (t,J=7.1 Hz, 2H), 1.72-1.45 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.92,144.86, 134.30, 131.57, 131.00, 130.34, 128.57, 127.41, 122.94, 121.55,37.10, 34.08, 28.08, 27.50; EIMS m/z 357, 359.

Preparation of2-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)isoindoline-1,3-dione(CA14)

The title compound was prepared from3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-ol(CA45) and isolated as a light yellow solid (4.49 g, 81%): ¹H NMR (400MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.18-8.02 (m, 2H), 7.96 (t, J=1.7 Hz, 1H),7.89 (dt, J=7.7, 1.5 Hz, 1H), 7.87-7.76 (m, 4H), 7.62 (d, J=8.5 Hz, 2H),7.40 (t, J=7.6 Hz, 1H), 7.34 (dt, J=7.7, 1.5 Hz, 1H), 3.65 (t, J=7.0 Hz,2H), 2.73 (t, J=7.7 Hz, 2H), 1.97 (p, J=7.5 Hz, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −56.98; ESIMS m/z 493 ([M+H]⁺).

Preparation of2-(4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)isoindoline-1,3-dione(CA15)

The title compound was prepared from4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-ol(CA24), further purified by trituration with diethyl ether/hexanes andisolated as a white solid (0.372 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ 8.64(s, 1H), 8.15-8.06 (m, 2H), 7.94-7.87 (m, 2H), 7.87-7.81 (m, 2H),7.81-7.77 (m, 2H), 7.71 (dd, J=5.5, 3.0 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H),3.73 (t, J=6.7 Hz, 2H), 2.73 (t, J=7.1 Hz, 2H), 1.82-1.65 (m, 4H); ¹⁹FNMR (376 MHz, CDCl₃) δ −62.48; ESIMS m/z 491 ([M+H]⁺).

Preparation of2-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)isoindoline-1,3-dione(CA16)

The title compound was prepared from4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-ol(CA25) and isolated as a white solid (2.39 g, 59%): ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 1H), 8.12-8.06 (m, 2H), 7.84 (dd, J=5.4, 3.0 Hz, 2H),7.83-7.77 (m, 2H), 7.75-7.66 (m, 2H), 7.38 (dd, J=9.2, 1.0 Hz, 2H), 7.29(d, J=8.2 Hz, 2H), 3.73 (t, J=6.7 Hz, 2H), 2.72 (t, J=7.1 Hz, 2H),1.85-1.61 (m, 4H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 507([M+H]⁺).

Preparation of2-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-yl)isoindoline-1,3-dione(CA17)

The title compound was prepared from4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-ol(CA23) and isolated as a white solid (0.393 g, 74%): ¹H NMR (400 MHz,CDCl₃) δ 8.56 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.88 (dd, J=5.5, 3.1 Hz,2H), 7.79 (d, J=8.9 Hz, 2H), 7.73 (dd, J=5.5, 3.0 Hz, 2H), 7.43 (d,J=8.3 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 4.00 (t, J=7.0 Hz, 2H), 2.86 (t,J=7.0 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 503([M+H]⁺).

Example 60: Preparation of2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)isoindoline-1,3-dione(C58)

To 2-(3-(4-bromophenyl)propyl)isoindoline-1,3-dione (C56) (6.46 g, 18.8mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (7.15g, 28.2 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.831 g,1.13 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (0.624 g, 1.13mmol) in a 200 mL round bottomed flask equipped with a stir bar andnitrogen was added potassium(II) acetate (5.53 g, 56.3 mmol) followed bydioxane (56.9 mL). The reaction mixture was evacuated and purged withnitrogen. The reaction was heated to 80° C. overnight. The reaction wascooled. The reaction was diluted with ethyl acetate and washed withwater. The aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated. Purification by flash column chromatographyusing 5-20% ethyl acetate/hexanes as eluent provided the title compoundas a yellow oil (7.41 g, 101%): ¹H NMR (400 MHz, CDCl₃) δ 7.82 (dd,J=5.4, 3.0 Hz, 2H), 7.72-7.67 (m, 4H), 7.23-7.17 (m, 2H), 3.74 (t, J=7.2Hz, 2H), 2.75-2.65 (m, 2H), 2.08-1.97 (m, 2H), 1.33 (s, 12H); ¹³C NMR(101 MHz, CDCl₃) δ 168.38, 144.40, 134.93, 133.84, 132.09, 127.73,123.17, 83.62, 60.40, 37.81, 33.42, 29.71, 24.85; ESIMS m/z 392([M+H]⁺).

Example 61: Preparation of2-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)isoindoline-1,3-dione(C59)

To 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (0.50g, 1.6 mmol),2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)isoindoline-1,3-dione(C58) (0.64 g, 1.6 mmol), sodium bicarbonate (0.27 g, 3.3 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.19 g, 0.16 mmol) in a 10-20mL microwave vial equipped with a stir bar was added dioxane (12 mL) andwater (4.1 mL). The reaction was capped and heated at 140° C. for 30minutes in a Biotage Initiator® microwave reactor with externalIR-sensor temperature monitoring from the side of the vessel. Themixture was diluted with ethyl acetate and washed with water. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered, andconcentrated. Purification by flash column chromatography using 0-30%ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provideda solid which was dried under house vacuum overnight. The title compoundwas obtained as a white solid (0.42 g, 53%): mp 145-148° C.; ¹H NMR (400MHz, CDCl₃) δ 8.54 (d, J=0.8 Hz, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.84 (ddd,J=5.5, 3.0, 0.8 Hz, 2H), 7.82-7.77 (m, 2H), 7.69 (ddd, J=5.5, 3.0, 0.8Hz, 2H), 7.38 (dt, J=9.0, 1.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 3.78 (t,J=7.2 Hz, 2H), 2.79-2.71 (m, 2H), 2.08 (p, J=7.5 Hz, 2H); ¹⁹F NMR (376MHz, CDCl₃) δ −58.03; ESIMS m/z 493 ([M+H]⁺).

Example 62: Preparation of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60)

To2-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)isoindoline-1,3-dione(C59) (0.373 g, 0.758 mmol) in a 25 mL vial equipped with a stir bar,Vigreux column, and nitrogen was added methanol (7.58 mL) followed byhydrazine monohydrate (0.110 mL, 2.27 mmol). The reaction was heated to50° C. until determined to be complete by LCMS. The reaction mixture wascooled to room temperature and diluted with dichloromethane. The layerswere separated and the aqueous layer was extracted with dichloromethane(2×). The organic layers were washed with sodium hydroxide (1 N, 4×),poured through a phase separator and concentrated. The resultant solidwas dried in vacuo over 72 hours at 50° C. to provide the title compoundas an off-white solid (0.262 g, 95%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.38(s, 1H), 8.10-8.04 (m, 2H), 8.04-7.98 (m, 2H), 7.66-7.59 (m, 2H), 7.35(d, J=8.1 Hz, 2H), 2.69-2.63 (m, 2H), 2.56 (t, J=6.9 Hz, 2H), 1.74-1.59(m, 2H), (NH₂ not observed); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMSm/z 363 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 62.

Preparation of3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18)

The title compound was prepared as described in Example 62 using2-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)isoindoline-1,3-dione(CA14) and isolated as a clear oil (3.49 g, 100%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.40 (s, 1H), 8.12-8.04 (m, 2H), 8.00-7.88 (m, 2H), 7.61 (d,J=8.6 Hz, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.31 (dt, J=7.7, 1.5 Hz, 1H),2.71 (q, J=9.0, 7.9 Hz, 2H), 2.57 (t, J=6.8 Hz, 2H), 1.74-1.62 (m, 2H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −57.01; ESIMS m/z 364 ([M+H]⁺).

Preparation of4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA19)

The title compound was prepared as described in Example 62 using2-(4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)isoindoline-1,3-dione(CA15), further purified with an SCX column and isolated as a yellowsolid (0.215 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 8.11 (d,J=8.2 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.30 (d,J=8.1 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 1.82-1.65 (m, 6H), 1.54 (d, J=8.1Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.48; ESIMS m/z 361 ([M+H]⁺).

Preparation of4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20)

The title compound was prepared as described in Example 62 using2-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)isoindoline-1,3-dione(CA16) and isolated as a white solid (1.76 g, 99%): ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 1H), 8.10 (d, J=8.2 Hz, 2H), 7.84-7.77 (m, 2H), 7.38(dt, J=8.1, 1.0 Hz, 2H), 7.33-7.27 (m, 2H), 2.78-2.65 (m, 4H), 1.76-1.64(m, 2H), 1.58-1.45 (m, 2H), 1.08 (bs, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ−58.03; ESIMS m/z 377 ([M+H]⁺).

Preparation of4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21)

The title compound was prepared as described in Example 62 using2-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)isoindoline-1,3-dione(CA2) and isolated as a light brown residue (1.94 g, 47%): ¹H NMR (400MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.13-8.05 (m, 2H), 7.98-7.89 (m, 2H),7.67-7.56 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.31 (dt, J=7.8, 1.5 Hz, 1H),2.67 (t, J=7.7 Hz, 2H), 2.57 (t, J=6.9 Hz, 2H), 1.64 (tt, J=9.2, 6.8 Hz,2H), 1.40 (p, J=7.1 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.98; ESIMSm/z 378 ([M+H]⁺).

Preparation of4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-amine(CA22)

The title compound was prepared as described in Example 62 using2-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-yl)isoindoline-1,3-dione(CA17), further purified using an SCX column and isolated as a yellowsolid (0.304 g, 104%): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.16-8.09(m, 2H), 7.84-7.76 (m, 2H), 7.56-7.48 (m, 2H), 7.44-7.34 (m, 2H), 2.95(t, J=6.3 Hz, 2H), 2.59 (t, J=6.3 Hz, 2H), (NH₂ not observed); ¹⁹F NMR(376 MHz, CDCl₃) δ −58.02; ESIMS m/z 373 ([M+H]⁺).

Example 63: Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(F21)

To3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) (0.231 g, 0.639 mmol) in a 25 mL vial equipped with a stir bar andnitrogen was added dichloromethane (4.3 mL), water (2.1 mL), and sodiumbicarbonate (0.161 g, 1.92 mmol). Triphosgene (0.0760 g, 0.255 mmol) wasadded in one portion and the reaction was stirred vigorously until theconversion of the starting material was observed by LCMS. The reactionmixture was diluted with dichloromethane, poured through a phaseseparator and concentrated. The resultant solid was suspended inacetonitrile (6.0 mL) in a 100 mL round bottomed flask equipped with astir bar and nitrogen. To this was added cesium carbonate (0.229 g,0.702 mmol) and 1-(2-isopropyl-5-methylphenyl)thiourea (0.133 g, 0.639mmol). The reaction was stirred overnight at room temperature. Themixture was diluted with ethyl acetate and washed with water. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered and concentrated.Purification by flash column chromatography using 0-30% ethyl acetate/B,where B=1:1 dichloromethane/hexanes, as eluent provided mixed fractions.The fractions were combined and re-purified by flash columnchromatography using 0-30% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent and the resultant solid was dried invacuo at 50° C. overnight to afford the title compound as a white solid(0.145 g, 38%).

The following compounds were prepared in accordance to the procedure inExample 63.

Preparation of1-(o-tolylcarbamothioyl)-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC92)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(o-tolyl)thiourea. Sodium acetate was used in place ofsodium bicarbonate. The title compound was isolated as a white solid(0.061 g, 21%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.06 (s,1H), 9.39 (s, 1H), 8.14-7.99 (m, 3H), 7.63 (dt, J=7.3, 1.3 Hz, 3H),7.45-7.35 (m, 2H), 7.33-7.14 (m, 4H), 7.09 (t, J=5.6 Hz, 1H), 3.17 (q,J=6.6 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.21 (s, 3H), 1.92-1.74 (m, 2H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 555 ([M+H]⁺), 553([M−H]⁻).

Preparation of1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC105)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(4-methoxy-2-methylphenyl)thiourea. Sodium acetate was usedin place of sodium bicarbonate. The title compound was isolated as awhite solid (0.119 g, 38%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H),10.00 (s, 1H), 9.39 (s, 1H), 8.16-7.98 (m, 4H), 7.70-7.57 (m, 2H), 7.38(dd, J=8.4, 1.9 Hz, 3H), 7.08 (t, J=5.7 Hz, 1H), 6.84 (d, J=2.9 Hz, 1H),6.77 (dd, J=8.7, 3.0 Hz, 1H), 3.75 (s, 3H), 3.16 (q, J=6.5 Hz, 2H), 2.70(dd, J=8.5, 6.7 Hz, 2H), 2.17 (s, 3H), 1.81 (p, J=7.2 Hz, 2H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z 585 ([M+H]⁺), 583 ([M−H]⁻).

Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC93)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(2-ethylphenyl)thiourea. Sodium acetate was used in place ofsodium bicarbonate. The title compound was isolated as a white solid(0.112 g, 37%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 10.07 (s,1H), 9.39 (s, 1H), 8.16-7.98 (m, 4H), 7.66-7.59 (m, 2H), 7.59-7.52 (m,1H), 7.43-7.35 (m, 2H), 7.31-7.19 (m, 3H), 7.10 (t, J=5.6 Hz, 1H), 3.17(q, J=6.5 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.55 (q, J=7.6 Hz, 2H),1.91-1.71 (m, 2H), 1.17-1.11 (m, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.97; ESIMS m/z 569 ([M+H]⁺), 567 ([M−H]⁻).

Preparation of1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC101)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39). Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.146 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H),10.07 (s, 1H), 9.39 (s, 1H), 8.14-8.00 (m, 4H), 7.68-7.59 (m, 2H),7.45-7.33 (m, 2H), 7.23-7.02 (m, 4H), 3.17 (q, J=6.6 Hz, 2H), 2.70 (t,J=7.6 Hz, 2H), 2.51 (p, J=1.9 Hz, 2H), 2.18 (s, 3H), 1.90-1.73 (m, 2H),1.12 (t, J=7.5 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z583 ([M+H]⁺), 581 ([M−H]⁻).

Preparation of1-[(2-isopropylphenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC94)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(2-isopropylphenyl)thiourea. Sodium acetate was used inplace of sodium bicarbonate. The title compound was isolated as a whitesolid (0.161 g, 31%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 10.08(s, 1H), 9.39 (s, 1H), 8.13-7.99 (m, 4H), 7.68-7.58 (m, 2H), 7.49-7.31(m, 4H), 7.24 (dtd, J=24.9, 7.4, 1.6 Hz, 2H), 7.09 (t, J=5.4 Hz, 1H),3.17 (q, J=6.5 Hz, 2H), 3.01 (p, J=6.8 Hz, 1H), 2.70 (t, J=7.7 Hz, 2H),1.82 (p, J=7.3 Hz, 2H), 1.17 (d, J=6.9 Hz, 6H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −56.96; ESIMS m/z 583 ([M+H]⁺), 581 ([M−H]⁻).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC102)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(2-isopropyl-4-methylphenyl)thiourea. Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.101 g, 32%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.87 (s, 1H),10.04 (s, 1H), 9.39 (s, 1H), 8.14-7.99 (m, 4H), 7.71-7.55 (m, 2H),7.46-7.33 (m, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.08(t, J=5.6 Hz, 1H), 7.04-6.95 (m, 1H), 3.17 (d, J=5.2 Hz, 2H), 2.96 (p,J=6.8 Hz, 1H), 2.70 (dd, J=8.6, 6.6 Hz, 2H), 2.31 (s, 3H), 1.81 (p,J=7.3 Hz, 2H), 1.16 (d, J=6.9 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.96; ESIMS m/z 597 ([M+H]⁺), 595 ([M−H]⁻).

Preparation of1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC103)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(4-fluoro-2-isopropylphenyl)thiourea. Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.116 g, 36%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H),10.11 (s, 1H), 9.39 (s, 1H), 8.15-7.97 (m, 4H), 7.63 (dd, J=8.7, 1.5 Hz,2H), 7.39 (dd, J=8.5, 5.7 Hz, 3H), 7.16 (dd, J=10.4, 3.0 Hz, 1H),7.12-6.97 (m, 2H), 3.26-3.11 (m, 2H), 3.05-2.89 (m, 1H), 2.70 (dd,J=8.6, 6.7 Hz, 2H), 1.92-1.71 (m, 2H), 1.16 (d, J=6.8 Hz, 6H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −56.97, −114.39; ESIMS m/z 601 ([M+H]⁺), 599([M−H]⁻).

Preparation of1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC99)

The title compound was prepared as described in Example 63 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(C60) and 1-(5-methyl-2-propylphenyl)thiourea (CA38). Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.111 g, 35%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H),10.04 (s, 1H), 9.39 (s, 1H), 8.14-7.98 (m, 4H), 7.62 (d, J=8.6 Hz, 2H),7.45-7.33 (m, 3H), 7.14 (d, J=7.8 Hz, 1H), 7.09 (t, J=5.7 Hz, 1H),7.05-6.98 (m, 1H), 3.17 (q, J=6.5 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H),2.49-2.41 (m, 2H), 2.27 (s, 3H), 1.81 (dt, J=13.7, 6.7 Hz, 2H), 1.50 (q,J=7.4 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.97; ESIMS m/z 597 ([M+H]⁺), 595 ([M−H]⁻).

Preparation of1-(o-tolylcarbamothioyl)-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC118)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(o-tolyl)thiourea. Sodium acetate was used in place ofsodium bicarbonate. The title compound was isolated as a white solid(0.075 g, 24%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 10.05 (s,1H), 9.40 (s, 1H), 8.12-8.04 (m, 2H), 8.01-7.92 (m, 2H), 7.68-7.57 (m,3H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.4 Hz, 1H), 7.29-7.24 (m,1H), 7.24-7.13 (m, 2H), 7.10 (t, J=5.7 Hz, 1H), 3.18 (q, J=6.5 Hz, 2H),2.73 (t, J=7.6 Hz, 2H), 2.20 (s, 3H), 1.93-1.74 (m, 2H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −56.96; ESIMS m/z 555 ([M+H]⁺), 553 ([M−H]⁻).

Preparation of1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC131)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(4-methoxy-2-methylphenyl)thiourea. Sodium acetate was usedin place of sodium bicarbonate. The title compound was isolated as awhite solid (0.103 g, 31%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H),10.00 (s, 1H), 9.40 (s, 1H), 8.13-8.04 (m, 2H), 8.02-7.92 (m, 2H),7.67-7.57 (m, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.42-7.30 (m, 2H), 7.08 (t,J=5.6 Hz, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.76 (dd, J=8.7, 2.9 Hz, 1H),3.74 (s, 3H), 3.17 (q, J=6.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.16 (s,3H), 1.93-1.72 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z585 ([M+H]⁺), 583 ([M−H]⁻).

Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC119)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(2-ethylphenyl)thiourea. Sodium acetate was used in placeof sodium bicarbonate. The title compound was isolated as a white solid(0.175 g, 55%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 10.07 (s,1H), 9.40 (s, 1H), 8.13-8.04 (m, 2H), 8.02-7.93 (m, 2H), 7.65-7.59 (m,2H), 7.55 (dt, J=6.5, 3.7 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt,J=7.7, 1.4 Hz, 1H), 7.31-7.24 (m, 1H), 7.21 (dd, J=5.8, 3.5 Hz, 2H),7.15-7.06 (m, 1H), 3.18 (q, J=6.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.55(t, J=7.5 Hz, 2H), 1.90-1.74 (m, 2H), 1.12 (t, J=7.5 Hz, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −56.98; ESIMS m/z 569 ([M+H]⁺), 567 ([M−H]⁻).

Preparation of1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC127)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39). Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.154 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H),10.07 (s, 1H), 9.41 (s, 1H), 8.13-8.05 (m, 2H), 8.03-7.92 (m, 2H), 7.62(dt, J=7.8, 1.1 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.5Hz, 1H), 7.21-7.14 (m, 1H), 7.14-7.04 (m, 3H), 3.18 (q, J=6.6 Hz, 2H),2.83-2.67 (m, 2H), 2.48 (d, J=2.6 Hz, 2H), 2.17 (s, 3H), 1.92-1.76 (m,2H), 1.11 (t, J=7.6 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMSm/z 583 ([M+H]⁺), 581 ([M−H]⁻).

Preparation of1-[(2-isopropylphenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC120)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(2-isopropylphenyl)thiourea. Sodium acetate was used inplace of sodium bicarbonate. The title compound was isolated as a whitesolid (0.131 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 10.07(s, 1H), 9.41 (s, 1H), 8.13-8.04 (m, 2H), 8.01-7.93 (m, 2H), 7.62 (ddd,J=7.9, 2.0, 1.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.41 (dd, J=7.8, 1.5Hz, 1H), 7.39-7.32 (m, 2H), 7.27 (td, J=7.5, 1.5 Hz, 1H), 7.20 (td,J=7.5, 1.7 Hz, 1H), 7.11 (t, J=5.6 Hz, 1H), 3.18 (q, J=6.5 Hz, 2H), 3.00(hept, J=6.8 Hz, 1H), 2.73 (t, J=7.7 Hz, 2H), 1.93-1.75 (m, 2H), 1.16(d, J=6.9 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z 583([M+H]⁺), 581 ([M−H]⁻).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC128)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(2-isopropyl-4-methylphenyl)thiourea. Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.123 g, 37%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.87 (s, 1H),10.04 (s, 1H), 9.41 (s, 1H), 8.12-8.04 (m, 2H), 8.02-7.91 (m, 2H), 7.61(ddd, J=7.9, 2.0, 1.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7,1.4 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.13 (d, J=1.9 Hz, 1H), 7.09 (t,J=5.6 Hz, 1H), 7.04-6.97 (m, 1H), 3.17 (q, J=6.5 Hz, 2H), 2.95 (hept,J=7.0 Hz, 1H), 2.82-2.64 (m, 2H), 2.30 (s, 3H), 1.91-1.77 (m, 2H), 1.14(d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 597([M+H]⁺), 595 ([M−H]⁻).

Preparation of1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC129)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(4-fluoro-2-isopropylphenyl)thiourea. Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.140 g, 41%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H),10.11 (s, 1H), 9.41 (s, 1H), 8.13-8.04 (m, 2H), 8.02-7.92 (m, 2H), 7.61(dq, J=7.8, 1.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.43-7.31 (m, 2H), 7.15(dd, J=10.4, 3.0 Hz, 1H), 7.10 (t, J=5.6 Hz, 1H), 7.03 (td, J=8.5, 3.0Hz, 1H), 3.26-3.10 (m, 2H), 2.97 (pd, J=6.9, 1.6 Hz, 1H), 2.73 (dd,J=8.5, 6.7 Hz, 2H), 1.90-1.76 (m, 2H), 1.15 (d, J=6.8 Hz, 6H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −56.97, −114.41; ESIMS m/z 601 ([M+H]⁺), 599([M−H]⁻).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC124)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(2-isopropyl-5-methylphenyl)thiourea. Sodium acetate wasused in place of sodium bicarbonate. The title compound was isolated asa white solid (0.118 g, 35%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s, 1H),10.05 (s, 1H), 9.40 (s, 1H), 8.13-8.04 (m, 2H), 8.03-7.93 (m, 2H), 7.61(d, J=8.6 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.8, 1.4 Hz, 1H),7.21 (dd, J=4.9, 3.0 Hz, 2H), 7.15-7.03 (m, 2H), 3.18 (q, J=6.5 Hz, 2H),2.95 (hept, J=6.7 Hz, 1H), 2.73 (t, J=7.7 Hz, 2H), 2.25 (s, 3H),1.90-1.76 (m, 2H), 1.13 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.98; ESIMS m/z 597 ([M+H]⁺), 595 ([M−H]⁻).

Preparation of1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC125)

The title compound was prepared as described in Example 63 using3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CA18) and 1-(5-methyl-2-propylphenyl)thiourea (CA38). Sodium acetatewas used in place of sodium bicarbonate. The title compound was isolatedas a white solid (0.134 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s,1H), 10.04 (s, 1H), 9.40 (s, 1H), 8.14-8.04 (m, 2H), 8.03-7.92 (m, 2H),7.68-7.57 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.11 (t,J=7.1 Hz, 2H), 7.01 (ddd, J=7.9, 1.7, 0.8 Hz, 1H), 3.18 (q, J=6.5 Hz,2H), 2.73 (dd, J=8.7, 6.6 Hz, 2H), 2.45 (dd, J=8.6, 6.6 Hz, 2H), 2.26(s, 3H), 1.91-1.75 (m, 2H), 1.55-1.41 (m, 2H), 0.84 (t, J=7.3 Hz, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.98; ESIMS m/z 597 ([M+H]⁺), 595([M−H]⁻).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC159)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA19) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as awhite solid (0.101 g, 37%): ¹H NMR (400 MHz, CDCl₃) δ 11.86 (bs, 1H),9.77 (bs, 1H), 8.65 (s, 1H), 8.19-8.03 (m, 2H), 7.91 (d, J=8.4 Hz, 2H),7.85-7.72 (m, 2H), 7.40-7.20 (m, 5H), 5.68 (bs, 1H), 3.29 (d, J=17.5 Hz,2H), 3.13-2.94 (m, 1H), 2.69 (t, J=7.5 Hz, 2H), 2.32 (s, 3H), 1.69 (s,2H), 1.56 (s, 2H), 1.21 (d, J=6.9 Hz, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ−62.48; ESIMS m/z 595 ([M+H]⁺).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC150)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as awhite solid (0.153 g, 38%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s, 1H),10.01 (s, 1H), 9.38 (s, 1H), 8.11-8.00 (m, 4H), 7.67-7.59 (m, 2H), 7.37(d, J=8.2 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 7.12-7.05 (m, 1H), 7.05-6.98(m, 1H), 3.17 (q, J=6.5 Hz, 2H), 2.94 (hept, J=6.7 Hz, 1H), 2.75-2.64(m, 2H), 2.25 (s, 3H), 1.73-1.59 (m, 2H), 1.58-1.43 (m, 2H), 1.13 (d,J=6.9 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z 611([M+H]⁺).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]but-3-ynyl]urea(PC160)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-amine(CA22) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as awhite solid (0.183 g, 39%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H),10.27 (s, 1H), 9.43 (s, 1H), 8.09 (m, 4H), 7.66-7.60 (m, 2H), 7.60-7.55(m, 2H), 7.25-7.18 (m, 3H), 7.09 (d, J=7.7 Hz, 1H), 3.40 (q, J=6.4 Hz,2H), 2.96 (hept, J=6.7 Hz, 1H), 2.68 (t, J=6.6 Hz, 2H), 2.26 (s, 3H),1.14 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z607 ([M+H]⁺).

Preparation of1-[(2-isopropylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC146)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2-isopropylphenyl)thiourea and isolated as a white solid(0.091 g, 38%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.02 (s,1H), 9.37 (s, 1H), 8.10-7.97 (m, 4H), 7.61 (d, J=8.6 Hz, 2H), 7.44-7.29(m, 4H), 7.29-7.14 (m, 2H), 7.01 (s, 1H), 3.23-3.11 (m, 2H), 3.04-2.90(m, 1H), 2.67 (t, J=7.4 Hz, 2H), 1.71-1.56 (m, 2H), 1.56-1.42 (m, 2H),1.14 (d, J=6.9 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z597 ([M+H]⁺).

Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC145)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2-ethylphenyl)thiourea and isolated as a white solid(0.111 g, 48%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.01 (s, 1H), 10.01 (s,1H), 9.37 (s, 1H), 8.09-7.98 (m, 4H), 7.61 (d, J=8.6 Hz, 2H), 7.53 (dd,J=5.6, 3.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.30-7.23 (m, 1H), 7.19 (dd,J=5.8, 3.5 Hz, 2H), 7.01 (s, 1H), 3.22-3.11 (m, 2H), 2.73-2.63 (m, 2H),2.52 (d, J=7.6 Hz, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.15-1.04 (m, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 583 ([M+H]⁺).

Preparation of1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC151)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(5-methyl-2-propylphenyl)thiourea (CA38) and isolated as awhite solid (0.110 g, 45%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.98 (s, 1H),9.97 (s, 1H), 9.36 (s, 1H), 8.03 (m, 4H), 7.60 (d, J=8.7 Hz, 2H), 7.35(m, 3H), 7.11 (d, J=7.8 Hz, 1H), 7.05-6.92 (m, 2H), 3.16 (q, J=6.3 Hz,2H), 2.66 (t, J=7.5 Hz, 2H), 2.42 (t, J=7.6 Hz, 2H), 2.24 (s, 3H),1.72-1.56 (m, 2H), 1.56-1.38 (m, 4H), 0.82 (t, J=7.3 Hz, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 611 ([M+H]⁺).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC154)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as awhite solid (0.100 g, 41%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.84 (s, 1H),9.97 (s, 1H), 9.36 (s, 1H), 8.11-7.96 (m, 4H), 7.60 (d, J=8.5 Hz, 2H),7.35 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 6.98 (d,J=8.0 Hz, 2H), 3.15 (q, J=6.3 Hz, 2H), 3.00-2.83 (m, 1H), 2.66 (t, J=7.6Hz, 2H), 2.28 (s, 3H), 1.72-1.55 (m, 2H), 1.55-1.42 (m, 2H), 1.12 (d,J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 611([M+H]⁺).

Preparation of1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC153)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) and isolated as awhite solid (0.141 g, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H),10.00 (s, 1H), 9.37 (s, 1H), 8.12-7.98 (m, 4H), 7.66-7.54 (m, 2H), 7.37(d, J=8.2 Hz, 2H), 7.24-7.13 (m, 1H), 7.11 (d, J=2.9 Hz, 2H), 7.00 (d,J=5.7 Hz, 1H), 3.18 (q, J=6.5 Hz, 2H), 2.75-2.61 (m, 2H), 2.49-2.44 (m,2H), 2.16 (s, 3H), 1.65 (q, J=7.7 Hz, 2H), 1.52 (q, J=7.3 Hz, 2H), 1.11(t, J=7.6 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 597([M+H]⁺).

Preparation of1-(o-tolylcarbamothioyl)-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC144)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(o-tolyl)thiourea and isolated as a white solid (0.097 g,43%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.98 (s, 1H), 9.37 (s,1H), 8.14-7.90 (m, 4H), 7.66-7.54 (m, 3H), 7.37 (d, J=8.1 Hz, 2H),7.31-7.23 (m, 1H), 7.23-7.14 (m, 2H), 7.02 (s, 1H), 3.23-3.12 (m, 2H),2.68 (t, J=7.5 Hz, 2H), 2.20 (s, 3H), 1.70-1.59 (m, 2H), 1.57-1.44 (m,2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 569 ([M+H]⁺).

Preparation of1-[(2,6-dimethylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea (PC152)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2,6-dimethylphenyl)thiourea and isolated as a white solid(0.122 g, 53%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 9.98 (s, 1H),9.37 (s, 1H), 8.11-8.00 (m, 4H), 7.66-7.58 (m, 2H), 7.37 (d, J=8.1 Hz,2H), 7.09 (q, J=5.2 Hz, 3H), 6.99 (t, J=5.7 Hz, 1H), 3.18 (q, J=6.5 Hz,2H), 2.69 (t, J=7.6 Hz, 2H), 2.15 (s, 6H), 1.66 (p, J=7.5 Hz, 2H), 1.51(p, J=6.9 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 583([M+H]⁺).

Preparation of1-[(2-isopropyl-5-methoxy-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC156)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) and isolatedas a white solid (0.114 g, 46%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s,1H), 10.01 (s, 1H), 9.36 (s, 1H), 8.13-7.97 (m, 4H), 7.68-7.56 (m, 2H),7.37 (d, J=8.1 Hz, 2H), 7.23 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H),7.01 (d, J=5.9 Hz, 1H), 6.84 (dd, J=8.6, 2.8 Hz, 1H), 3.71 (s, 3H), 3.18(q, J=6.5 Hz, 2H), 2.92 (hept, J=6.9 Hz, 1H), 2.68 (t, J=7.6 Hz, 2H),1.65 (p, J=7.6 Hz, 2H), 1.51 (q, J=7.2 Hz, 2H), 1.13 (d, J=6.8 Hz, 6H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z 627 ([M+H]⁺).

Preparation of1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC155)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as awhite solid (0.089 g, 36%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H),10.04 (s, 1H), 9.37 (s, 1H), 8.11-7.99 (m, 4H), 7.61 (d, J=8.8 Hz, 2H),7.44-7.31 (m, 3H), 7.14 (dd, J=10.4, 2.9 Hz, 1H), 7.09-6.96 (m, 2H),3.18 (q, J=6.5 Hz, 2H), 3.03-2.90 (m, 1H), 2.68 (t, J=7.5 Hz, 2H),1.70-1.58 (m, 2H), 1.56-1.44 (m, 2H), 1.15 (d, J=6.8 Hz, 6H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −56.97, −114.40; ESIMS m/z 615 ([M+H]⁺).

Preparation of1-(o-tolylcarbamothioyl)-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC170)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(o-tolyl)thiourea and isolated as a white solid (0.102 g,35%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 10.01 (s, 1H), 9.39 (s,1H), 8.11-8.05 (m, 2H), 7.98 (t, J=1.7 Hz, 1H), 7.94 (dt, J=7.7, 1.4 Hz,1H), 7.67-7.57 (m, 3H), 7.44 (t, J=7.6 Hz, 1H), 7.34 (dt, J=7.7, 1.5 Hz,1H), 7.28-7.23 (m, 1H), 7.23-7.13 (m, 2H), 7.03 (t, J=5.7 Hz, 1H), 3.19(q, J=6.5 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 2.19 (s, 3H), 1.74-1.60 (m,2H), 1.52 (p, J=6.9 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMSm/z 569 ([M+H]⁺).

Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC171)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(2-ethylphenyl)thiourea and isolated as a white solid(0.113 g, 38%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 10.04 (s,1H), 9.41 (s, 1H), 8.13-8.06 (m, 2H), 8.00 (d, J=1.7 Hz, 1H), 7.96 (dt,J=7.7, 1.4 Hz, 1H), 7.69-7.60 (m, 2H), 7.56 (dd, J=5.6, 3.6 Hz, 1H),7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.5 Hz, 1H), 7.31-7.26 (m, 1H),7.26-7.19 (m, 2H), 7.05 (t, J=5.6 Hz, 1H), 3.21 (q, J=6.5 Hz, 2H), 2.74(t, J=7.6 Hz, 2H), 2.59-2.53 (m, 2H), 1.69 (tt, J=9.0, 6.6 Hz, 2H), 1.54(p, J=6.9 Hz, 2H), 1.12 (t, J=7.5 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.96; ESIMS m/z 583 ([M+H]⁺).

Preparation of1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC179)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) and isolated as awhite solid (0.143 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H),10.04 (s, 1H), 9.40 (s, 1H), 8.12-8.06 (m, 2H), 8.00 (t, J=1.6 Hz, 1H),7.96 (dt, J=7.7, 1.4 Hz, 1H), 7.64 (ddt, J=7.8, 1.9, 0.9 Hz, 2H), 7.46(t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.4 Hz, 1H), 7.22-7.15 (m, 1H), 7.10(dq, J=6.3, 1.8 Hz, 2H), 7.02 (t, J=5.7 Hz, 1H), 3.21 (q, J=6.5 Hz, 2H),2.74 (t, J=7.6 Hz, 2H), 2.48 (td, J=7.5, 1.9 Hz, 2H), 2.17 (s, 3H), 1.69(p, J=7.6 Hz, 2H), 1.62-1.48 (m, 2H), 1.11 (t, J=7.6 Hz, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z 597 ([M+H]⁺).

Preparation of1-[(2-isopropylphenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC172)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(2-isopropylphenyl)thiourea and isolated as a white solid(0.072 g, 24%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 10.05 (s,1H), 9.41 (s, 1H), 8.13-8.07 (m, 2H), 8.00 (t, J=1.7 Hz, 1H), 7.96 (dt,J=7.8, 1.4 Hz, 1H), 7.64 (dq, J=7.7, 1.0 Hz, 2H), 7.46 (t, J=7.6 Hz,1H), 7.42 (dd, J=7.9, 1.5 Hz, 1H), 7.36 (ddd, J=7.8, 3.3, 1.6 Hz, 2H),7.28 (td, J=7.5, 1.5 Hz, 1H), 7.21 (td, J=7.5, 1.7 Hz, 1H), 7.05 (t,J=5.7 Hz, 1H), 3.21 (q, J=6.4 Hz, 2H), 3.00 (p, J=6.9 Hz, 1H), 2.74 (t,J=7.6 Hz, 2H), 1.69 (p, J=7.8 Hz, 2H), 1.54 (p, J=7.0 Hz, 2H), 1.16 (d,J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z 597([M+H]⁺).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC180)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as awhite solid (0.139 g, 45%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H),10.01 (s, 1H), 9.40 (s, 1H), 8.13-8.07 (m, 2H), 8.00 (d, J=1.7 Hz, 1H),7.96 (dt, J=7.7, 1.4 Hz, 1H), 7.64 (dq, J=7.8, 1.0 Hz, 2H), 7.46 (t,J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.4 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H),7.15 (dd, J=2.0, 0.9 Hz, 1H), 7.07-6.97 (m, 2H), 3.20 (q, J=6.5 Hz, 2H),2.95 (p, J=6.9 Hz, 1H), 2.74 (t, J=7.6 Hz, 2H), 2.32 (s, 3H), 1.68 (p,J=7.3 Hz, 2H), 1.61-1.47 (m, 2H), 1.15 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −56.96; ESIMS m/z 611 ([M+H]⁺).

Preparation of1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC181)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as awhite solid (0.114 g, 36%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.87 (s, 1H),10.09 (s, 1H), 9.41 (s, 1H), 8.13-8.07 (m, 2H), 8.00 (t, J=1.6 Hz, 1H),7.96 (dt, J=7.7, 1.4 Hz, 1H), 7.69-7.61 (m, 2H), 7.46 (t, J=7.6 Hz, 1H),7.43-7.33 (m, 2H), 7.16 (dd, J=10.4, 3.0 Hz, 1H), 7.05 (td, J=8.3, 2.9Hz, 2H), 3.20 (q, J=6.5 Hz, 2H), 3.05-2.90 (m, 1H), 2.74 (t, J=7.6 Hz,2H), 1.76-1.62 (m, 2H), 1.61-1.48 (m, 2H), 1.15 (d, J=6.8 Hz, 6H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −56.96, −114.42; ESIMS m/z 615 ([M+H]⁺).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC176)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as awhite solid (0.119 g, 38%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H),10.03 (s, 1H), 9.41 (s, 1H), 8.13-8.07 (m, 2H), 8.00 (t, J=1.7 Hz, 1H),7.96 (dt, J=7.6, 1.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.46 (t, J=7.6 Hz, 1H),7.36 (dt, J=7.6, 1.5 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.13-7.07 (m, 1H),7.04 (t, J=5.5 Hz, 1H), 3.20 (q, J=6.5 Hz, 2H), 2.95 (p, J=6.9 Hz, 1H),2.74 (t, J=7.6 Hz, 2H), 2.27 (s, 3H), 1.78-1.62 (m, 2H), 1.61-1.46 (m,2H), 1.14 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMSm/z 611 ([M+H]⁺).

Preparation of1-[(2-isopropyl-5-methoxy-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC182)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) and isolatedas a white solid (0.141 g, 44%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s,1H), 10.03 (s, 1H), 9.39 (s, 1H), 8.12-8.04 (m, 2H), 7.98 (t, J=1.6 Hz,1H), 7.94 (dt, J=7.7, 1.4 Hz, 1H), 7.62 (ddd, J=7.7, 1.9, 1.0 Hz, 2H),7.45 (t, J=7.6 Hz, 1H), 7.34 (dt, J=7.7, 1.5 Hz, 1H), 7.23 (d, J=8.7 Hz,1H), 7.10 (d, J=2.7 Hz, 1H), 7.03 (t, J=5.6 Hz, 1H), 6.84 (dd, J=8.7,2.8 Hz, 1H), 3.71 (s, 3H), 3.18 (q, J=6.4 Hz, 2H), 2.91 (p, J=6.8 Hz,1H), 2.72 (t, J=7.6 Hz, 2H), 1.67 (p, J=7.7 Hz, 2H), 1.52 (p, J=6.9 Hz,2H), 1.12 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMSm/z 627 ([M+H]⁺).

Preparation of1-[(2,4-dimethylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(FB16)

The title compound was prepared as described in Example 63 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA20) and 1-(2,4-dimethylphenyl)thiourea and isolated as a white solid(0.106 g, 46%).

Preparation of1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(FB36)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as a whitesolid (0.082 g, 27%).

Preparation of1-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(FB37)

The title compound was prepared as described in Example 63 using4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-amine(CA21) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) and isolated asa white solid (0.098 g, 31%).

Example 64: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(F20)

To1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(F21) (0.110 g, 0.184 mmol) in a 25 mL vial equipped with a stir bar andVigreux column was added sodium acetate (0.0600 g, 0.735 mmol), ethanol(2 mL) and methyl bromoacetate (0.0250 mL, 0.276 mmol). The reaction washeated to 70° C. overnight. The reaction was cooled and diluted withdichloromethane. The layers were separated and the aqueous layer wasextracted with dichloromethane. The organic layers were poured through aphase separator and concentrated. Purification by flash columnchromatography using 0-30% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent provided a solid which was driedovernight at 50° C. in vacuo to afford the title compound as a whitesolid (0.0791 g, 68%).

The following compounds were prepared in accordance to the procedure inExample 64.

Preparation of(Z)-1-(4-oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P92)

The title compound was prepared as described in Example 64 using1-(o-tolylcarbamothioyl)-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC92) and isolated as a light yellow solid (0.036 g, 72%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P105)

The title compound was prepared as described in Example 64 using1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC105) and isolated as a light yellow solid (0.085 g, 75%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P93, P510)

The title compound was prepared as described in Example 64 using1-[(2-ethylphenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC93) and isolated as a light yellow solid (0.057 g, 54%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P101)

The title compound was prepared as described in Example 64 using1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC101) and isolated as a light yellow solid (0.059 g, 41%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P94, P197)

The title compound was prepared as described in Example 64 using1-[(2-isopropylphenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC94) and isolated as a light yellow solid (0.071 g, 80%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P102)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC102) and isolated as a light yellow solid (0.070 g, 75%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P103, P1150)

The title compound was prepared as described in Example 64 using1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC103) and isolated as a light yellow solid (0.084 g, 77%).

Preparation of(Z)-1-(3-(5-methyl-2-propylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P99, P830)

The title compound was prepared as described in Example 64 using1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC99) and isolated as a light yellow solid (0.075 g, 72%).

Preparation of(Z)-1-(4-oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P118)

The title compound was prepared as described in Example 64 using1-(o-tolylcarbamothioyl)-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC118) and isolated as an off-white solid (0.051 g, 80%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P131)

The title compound was prepared as described in Example 64 using1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC131) and isolated as an off-white solid (0.074 g, 89%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P119)

The title compound was prepared as described in Example 64 using1-[(2-ethylphenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC119) and isolated as an off-white solid (0.071 g, 83%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P127)

The title compound was prepared as described in Example 64 using1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC127) and isolated as an off-white solid (0.061 g, 43%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P120)

The title compound was prepared as described in Example 64 using1-[(2-isopropylphenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC120) and isolated as an off-white solid (0.091 g, 80%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P128)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC128) and isolated as an off-white solid (0.091 g, 84%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P129)

The title compound was prepared as described in Example 64 using1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC129) and isolated as an off-white solid (0.095 g, 81%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P124)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC124) and isolated as an off-white solid (0.077 g, 80%).

Preparation of(Z)-1-(3-(5-methyl-2-propylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(P125)

The title compound was prepared as described in Example 64 using1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[3-[3-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea(PC125) and isolated as an off-white solid (0.097 g, 86%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P159)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC159) and isolated as a white solid (0.063 g, 70%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-yl)urea(P160)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]but-3-ynyl]urea(PC160) and isolated as a yellow solid (0.122 g, 74%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P150, P363)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC150) and isolated as a white solid (0.068 g, 78%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P146, P208)

The title compound was prepared as described in Example 64 using1-[(2-isopropylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC146) isolated as a white solid (0.063 g, 80%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P145, P522)

The title compound was prepared as described in Example 64 using1-[(2-ethylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC145) and isolated as a white solid (0.084 g, 83%).

Preparation of(Z)-1-(3-(5-methyl-2-propylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P151, P842)

The title compound was prepared as described in Example 64 using1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC151) and isolated as a white solid (0.081 g, 81%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P154)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC154) and isolated as a white solid (0.070 g, 82%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P153)

The title compound was prepared as described in Example 64 using1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC153) and isolated as a white foam (0.059 g, 52%).

Preparation of(Z)-1-(4-oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P144)

The title compound was prepared as described in Example 64 using1-(o-tolylcarbamothioyl)-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC144) and isolated as a white foam (0.070 g, 76%).

Preparation of(Z)-1-(3-(2,6-dimethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P152, P1481)

The title compound was prepared as described in Example 64 using1-[(2,6-dimethylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC152) and isolated as a white solid (0.078 g, 72%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P156, P682)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methoxy-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC156) and isolated as a white solid (0.089 g, 82%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P155, P1162)

The title compound was prepared as described in Example 64 using1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC155) and isolated as a white foam (0.075 g, 88%).

Preparation of(Z)-1-(4-oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P170)

The title compound was prepared as described in Example 64 using1-(o-tolylcarbamothioyl)-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl])-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC170) and isolated as a white solid (0.061 g, 72%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P171)

The title compound was prepared as described in Example 64 using1-[(2-ethylphenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC171) and isolated as a white solid (0.078 g, 77%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P179)

The title compound was prepared as described in Example 64 using1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC179) and isolated as a white solid (0.048 g, 37%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P172)

The title compound was prepared as described in Example 64 using1-[(2-isopropylphenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC172) and isolated as a white solid (0.048 g, 80%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P180)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC180) and isolated as a white solid (0.086 g, 66%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P181)

The title compound was prepared as described in Example 64 using1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC181) and isolated as a white solid (0.058 g, 57%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P176)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC176) and isolated as a white solid (0.076 g, 74%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(P182)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methoxy-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(PC182) and isolated as a white solid (0.064 g, 58%).

Preparation of(Z)-1-(4-oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P74)

The title compound was prepared as described in Example 64 using1-(o-tolylcarbamothioyl)-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC74) and isolated as a white solid (0.076 g, 77%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P87)

The title compound was prepared as described in Example 64 using1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC87) and isolated as a white solid (0.079 g, 84%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P75)

The title compound was prepared as described in Example 64 using1-[(2-ethylphenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC75) and isolated as a white solid (0.071 g, 73%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P83)

The title compound was prepared as described in Example 64 using1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC83) and isolated as a white solid (0.042 g, 34%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P76)

The title compound was prepared as described in Example 64 using1-[(2-isopropylphenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC76) and isolated as a white solid (0.026 g, 72%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P84)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC84) and isolated as a white solid (0.056 g, 77%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P85)

The title compound was prepared as described in Example 64 using1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC85) and isolated as a white solid (0.063 g, 77%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P81)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC81) and isolated as a yellow solid (0.014 g, 68%).

Preparation of(Z)-1-(3-(5-methyl-2-propylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P80)

The title compound was prepared as described in Example 64 using1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC80) and isolated as a white solid (0.076 g, 74%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB3)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[2-[2-methyl-4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(FB1) at a temperature of 60° C. and followed by reverse phasechromatography; isolated as a yellow wax (0.016 g, 10%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methoxyphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB4)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methoxy-phenyl)carbamothioyl]-3-[2-[2-methyl-4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(FB2) at a temperature of 60° C. and followed by reverse phasechromatography isolated as a light yellow solid (0.034 g, 19%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB6)

The title compound was prepared as described in Example 64 using1-[(2-ethylphenyl)carbamothioyl]-3-[2-[2-methyl-4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(FB5) at a temperature of 60° C. and followed by reverse phasechromatography; isolated as a pink solid (0.010 g, 7%).

Preparation of(Z)-1-(3-(2,4-dimethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(FB17)

The title compound was prepared as described in Example 64 using1-[(2,4-dimethylphenyl)carbamothioyl]-3-[4-[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(FB16) and isolated as a white foam (0.078 g, 83%).

Preparation of(Z)-1-(4-oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB27)

The title compound was prepared as described in Example 64 using1-(o-tolylcarbamothioyl)-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB18) and isolated as an off-white solid (0.090 g, 68%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB28)

The title compound was prepared as described in Example 64 using1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB19) and isolated as a light orange solid (0.042 g, 88%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB29)

The title compound was prepared as described in Example 64 using1-[(2-ethylphenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB20) and isolated as a white solid (0.078 g, 57%).

Preparation of(Z)-1-(3-(2-ethyl-6-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB30)

The title compound was prepared as described in Example 64 using1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FA21) and isolated as a white solid (0.035 g, 17%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB31)

The title compound was prepared as described in Example 64 using1-[(2-isopropylphenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FA22) and isolated as a light yellow solid (0.115 g, 57%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB32)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB23) and isolated as a light orange solid (0.144 g, 70%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB33)

The title compound was prepared as described in Example 64 using1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB24) and isolated as an off-white solid (0.097 g, 44%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB34)

The title compound was prepared as described in Example 64 using1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB25) and isolated as an off-white solid (0.091 g, 56%).

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(FB35)

The title compound was prepared as described in Example 64 using1-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB26) and isolated as a light yellow solid (0.095 g, 62%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(FB38)

The title compound was prepared as described in Example 64 using1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(FB36) and isolated as a white solid (0.048 g, 67%).

Preparation of(Z)-1-(3-(5-chloro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butyl)urea(FB39)

The title compound was prepared as described in Example 64 using1-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[4-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]butyl]urea(FB37) and isolated as a white solid (0.060 g, 58%).

Example 65: Preparation of4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-ol(C61)

To 3-(4-bromophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole(C53) (0.50 g, 1.4 mmol) in a 25 mL vial equipped with a stir bar andcap with septa was added bis(triphenylphosphine)palladium(II) chloride(0.019 g, 0.027 mmol), copper(I) iodide (0.0026 g, 0.014 mmol) andtriethylamine (8.5 mL) followed by but-3-yn-1-ol (0.12 mL, 1.6 mmol).The reaction was heated to 60° C. overnight. The reaction was stoppedand cooled to room temperature. The reaction mixture was treated with50% ethyl acetate/water. The aqueous layer was extracted with ethylacetate. The combined organic layers were washed with water. The organiclayer was dried over sodium sulfate, filtered, and concentrated.Purification by flash column chromatography using 0-50% ethyl acetate/B,where B=1:1 dichloromethane/hexanes, as eluent provided a solid whichwas dried overnight at 50° C. in vacuo to afford the title compound as atan solid. It was calculated based on ¹H NMR to be mixed with thestarting butynol (8%), (0.38 g, 71%): ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s,1H), 8.20-8.11 (m, 2H), 7.94-7.88 (m, 2H), 7.83-7.76 (m, 2H), 7.56-7.50(m, 2H), 3.85 (q, J=6.3 Hz, 2H), 2.74 (t, J=6.2 Hz, 2H), 1.83 (t, J=6.3Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.51; ESIMS m/z 358 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 65.

Preparation of4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-ol(CA23)

The title compound was prepared as described in Example 65 using3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C52), further purified by trituration with diethyl ether/hexanes andisolated as a white solid (5.46 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 8.57(s, 1H), 8.19-8.08 (m, 2H), 7.84-7.76 (m, 2H), 7.57-7.49 (m, 2H), 7.39(dq, J=8.8, 0.9 Hz, 2H), 3.85 (q, J=6.3 Hz, 2H), 2.73 (t, J=6.3 Hz, 2H),1.83 (t, J=6.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02; ESIMS m/z 374([M+H]⁺).

Example 66: Preparation of4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-ol(CA24)

To4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-ol(C61) (0.376 g, 0.967 mmol) in a 100 mL round bottomed flask equippedwith a stir bar and septa was added ethyl acetate (9.67 mL) followed bypalladium on carbon (0.103 g, 0.0970 mmol). The reaction mixture wasevacuated with vacuum and purged with hydrogen (balloon) (2×) andstirred at room temperature overnight. The reaction mixture was filteredthrough Celite®, washed with ethyl acetate and concentrated to providethe title compound as a white solid (0.363 g, 104%): ¹H NMR (400 MHz,CDCl₃) δ 8.65 (s, 1H), 8.15-8.08 (m, 2H), 7.94-7.88 (m, 2H), 7.80 (dd,J=8.2, 1.1 Hz, 2H), 7.34-7.28 (m, 2H), 3.74-3.66 (m, 2H), 3.66-3.60 (m,1H), 2.72 (t, J=7.6 Hz, 2H), 1.81-1.71 (m, 2H), 1.69-1.60 (m, 2H); ¹⁹FNMR (376 MHz, CDCl₃) δ −62.48; ESIMS m/z 362 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 66.

Preparation of4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butan-1-ol(CA25)

The title compound was prepared as described in Example 66 using4-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-ol(CA23) and isolated as a white solid (3.03 g, 100%): ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 1H), 8.10 (d, J=8.2 Hz, 2H), 7.86-7.76 (m, 2H), 7.39(dq, J=9.0, 0.9 Hz, 2H), 7.33-7.27 (m, 2H), 3.73-3.59 (m, 3H), 2.72 (t,J=7.6 Hz, 2H), 1.82-1.70 (m, 2H), 1.70-1.59 (m, 2H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.03; ESIMS m/z 378 ([M+H]⁺).

Preparation of 5-methyl-2-propylaniline (CA26)

The title compound was prepared as described in Example 66 using1-allyl-4-methyl-2-nitrobenzene (CA30) and isolated as a yellow liquid(1.39 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 6.92 (d, J=7.6 Hz, 1H), 6.55(d, J=7.6 Hz, 1H), 6.51 (s, 1H), 3.55 (s, 2H), 2.47-2.37 (m, 2H), 2.24(s, 3H), 1.69-1.53 (m, 2H), 0.99 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 143.91, 136.52, 129.46, 123.83, 119.49, 116.29, 33.05, 22.10,21.05, 14.19; EIMS m/z 149 ([M]⁺).

Preparation of 2-isopropyl-5-methoxyaniline (CA27)

The title compound was prepared as described in Example 66 using4-methoxy-2-nitro-1-(prop-1-en-2-yl)benzene (CA43) and isolated as ayellow liquid (2.23 g, 95%): ¹H NMR (400 MHz, CDCl₃) δ 7.03 (d, J=8.4Hz, 1H), 6.35 (dd, J=8.5, 2.6 Hz, 1H), 6.25 (d, J=2.6 Hz, 1H), 3.75 (s,3H), 3.65 (s, 2H), 2.83 (p, J=6.8 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H); EIMSm/z 165 ([M]⁺).

Preparation of 2-ethyl-5-methylaniline (CA28)

The title compound was prepared as described in Example 66 using4-methyl-2-nitro-1-vinylbenzene (CA31) and isolated as a yellow liquid(0.926 g, 88%): ¹H NMR (400 MHz, CDCl₃) δ 6.95 (d, J=7.6 Hz, 1H), 6.57(d, J=7.6 Hz, 1H), 6.52 (s, 1H), 3.56 (s, 2H), 2.48 (q, J=7.5 Hz, 2H),2.25 (s, 3H), 1.23 (t, J=7.6 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 143.80,136.48, 128.32, 125.22, 119.59, 116.15, 23.67, 21.03, 13.24; EIMS m/z135 ([M]⁺).

Preparation of 2-ethyl-4-methylaniline (CA29)

The title compound was prepared as described in Example 66 using5-methyl-2-nitro-1-vinylbenzene (CA32) and isolated as a brown liquid(1.07 g, 88%): ¹H NMR (400 MHz, CDCl₃) δ 6.88 (s, 1H), 6.86-6.82 (m,1H), 6.60 (d, J=7.9 Hz, 1H), 3.55 (s, 2H), 2.50 (q, J=7.5 Hz, 2H), 2.24(s, 3H), 1.24 (t, J=7.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 141.35,129.09, 128.25, 128.01, 127.19, 115.56, 24.05, 20.55, 13.17; EIMS m/z135 ([M]⁺).

Preparation of 5-chloro-2-isopropylaniline (CB27)

The title compound was prepared as described in Example 66 using4-chloro-2-nitro-1-(prop-1-en-2-yl)benzene (CB33) and isolated as abrown liquid (1.82 g, 84%): ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.31 (m, 1H),7.22-7.16 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.83-6.77 (m, 2H), 2.90 (p,J=6.8 Hz, 1H), 1.25 (d, J=6.8 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ126.91, 126.83, 126.51, 121.34, 120.07, 116.37, 27.44, 22.34; EIMS m/z169 ([M]⁺).

Preparation of2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB28)

The title compound was prepared as described in Example 66 usingbenzyl(2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)carbamate(CB67) and methanol as solvent; isolated as a yellow gum (0.775 g, 92%):¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.13 (d, J=8.2 Hz, 2H), 7.81 (d,J=9.0 Hz, 2H), 7.39 (dd, J=9.1, 1.0 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H),2.74 (s, 2H), 2.05 (s, 2H), 1.16 (s, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ−58.03; ESIMS m/z 377 ([M+H]⁺).

Preparation of2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CB29)

The title compound was prepared as described in Example 66 usingbenzyl(2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)carbamate(CB68) and methanol as solvent; isolated as a clear oil (0.427 g, 80%):¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.15 (d, J=8.4 Hz, 2H),7.84-7.77 (m, 2H), 7.49-7.42 (m, 2H), 7.39 (dt, J=7.9, 1.0 Hz, 2H), 2.85(s, 2H), 1.78 (s, 2H), 1.36 (s, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03;ESIMS m/z 377 ([M+H]⁺).

Preparation of1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanamine(CB30)

The title compound was prepared as described in Example 66 usingbenzyl(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropyl)carbamate(CB69) and isolated as a tan oil (0.392 g, 95%): ¹H NMR (400 MHz, CDCl₃)δ 8.60-8.49 (m, 1H), 8.19-8.06 (m, 2H), 7.84-7.72 (m, 2H), 7.44-7.29 (m,4H), 3.49 (s, 2H), 2.17 (s, 3H), 0.73-0.59 (m, 4H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.03; ESIMS m/z 375 ([M+H]⁺).

Example 67: Preparation of 1-allyl-4-methyl-2-nitrobenzene (CA30)

To 1-chloro-4-methyl-2-nitrobenzene (2.00 g, 11.7 mmol),allyltributylstannane (5.79 g, 17.5 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.818 g, 1.17 mmol) intwo 25-mL reaction vials was added 1,2-dichloroethane (20 mL). The vialswere capped and heated at 120° C. for 45 minutes in a Biotage Initiator®microwave reactor with an external IR-sensor temperature monitoring fromthe side of the vessel. The reaction mixture was loaded onto a Celite®cartridge. The crude material was purified by flash columnchromatography using 0-50% ethyl acetate/hexanes as eluent followed byreverse-phase flash column chromatography using 0-100%acetonitrile/water as eluent. The combined acetonitrile/water fractionswere concentrated, extracted with ethyl acetate, dried over sodiumsulfate, filtered, concentrated, and dried in a vacuum oven to providethe title compound as a yellow liquid (1.76 g, 84%): ¹H NMR (400 MHz,CDCl₃) δ 7.73 (d, J=0.9 Hz, 1H), 7.34 (dd, J=7.8, 1.2 Hz, 1H), 7.24 (d,J=7.8 Hz, 1H), 5.96 (ddt, J=16.6, 10.1, 6.4 Hz, 1H), 5.08 (ddq, J=18.5,17.0, 1.5 Hz, 2H), 3.64 (d, J=6.4 Hz, 2H), 2.40 (s, 3H); ¹³C NMR (101MHz, CDCl₃) δ 149.09, 137.62, 135.35, 133.81, 131.81, 131.72, 124.94,116.81, 36.62, 20.72; EIMS m/z 176 ([M]⁺).

The following compounds were prepared in accordance to the procedure inExample 67.

Preparation of 4-methyl-2-nitro-1-vinylbenzene (CA31)

The title compound was prepared as described in Example 67 using1-chloro-4-methyl-2-nitrobenzene and tributyl(vinyl)stannane, furtherpurified by flash column chromatography and reverse phase chromatographyand isolated as a yellow liquid (1.26 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ7.73 (d, J=0.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.46-7.35 (m, 1H), 7.13(dd, J=17.3, 11.0 Hz, 1H), 5.71 (dd, J=17.3, 0.9 Hz, 1H), 5.43 (dd,J=11.0, 0.9 Hz, 1H), 2.42 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 147.71,138.91, 133.92, 132.31, 130.52, 128.22, 124.63, 118.10, 20.88; EIMS m/z163 ([M]⁺).

Preparation of 5-methyl-2-nitro-1-vinylbenzene (CA32)

The title compound was prepared as described in Example 67 using1-chloro-4-methyl-2-nitrobenzene and tributyl(vinyl)stannane, furtherpurified by flash column chromatography and reverse phase chromatographyand isolated as a yellow liquid (1.46 g, 75%): ¹H NMR (400 MHz, CDCl₃) δ7.88 (d, J=8.3 Hz, 1H), 7.40 (d, J=1.2 Hz, 1H), 7.21 (ddd, J=11.0, 9.9,8.2 Hz, 2H), 5.71 (dd, J=17.3, 1.0 Hz, 1H), 5.46 (dd, J=11.0, 1.0 Hz,1H), 2.44 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 145.56, 144.31, 133.64,133.05, 129.08, 128.98, 124.68, 118.52, 21.49; EIMS m/z 163 ([M]⁺).

Example 68: Preparation ofN-((5-methyl-2-propylphenyl)carbamothioyl)benzamide (CA33)

To 5-methyl-2-propylaniline (CA26) (1.38 g, 9.22 mmol) and benzoylisothiocyanate (1.24 mL, 9.22 mmol) was added acetone (13 mL). Thereaction was heated at 60° C. for 4 h. The reaction was cooled andconcentrated. The resulting oil was dried in a vacuum oven overnightproviding the title compound as a brown oil (3.26 g, 100%): ¹H NMR (400MHz, CDCl₃) δ 12.20 (s, 1H), 9.15 (s, 1H), 7.92 (dt, J=8.5, 1.7 Hz, 2H),7.71-7.60 (m, 1H), 7.55 (m, 3H), 7.18 (d, J=7.8 Hz, 1H), 7.09 (dd,J=7.8, 1.1 Hz, 1H), 2.66-2.55 (m, 2H), 2.36 (s, 3H), 1.72-1.57 (m, 2H),0.97 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 179.64, 166.90,136.22, 135.72, 134.57, 133.74, 131.68, 129.79, 129.22, 128.64, 127.55,127.24, 33.28, 23.58, 21.01, 13.98; ESIMS m/z 313 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 68.

Preparation of N-((2-ethyl-6-methylphenyl)carbamothioyl)benzamide (CA34)

The title compound was prepared as described in Example 68 using2-ethyl-6-methylaniline and isolated as a yellow liquid (6.41 g, 100%):¹H NMR (400 MHz, CDCl₃) δ 11.88 (s, 1H), 9.21 (s, 1H), 8.02-7.85 (m,2H), 7.73-7.63 (m, 1H), 7.62-7.50 (m, 2H), 7.29-7.23 (m, 1H), 7.20-7.14(m, 2H), 2.75-2.57 (m, 2H), 2.33 (s, 3H), 1.25 (t, J=7.6 Hz, 3H); ESIMSm/z 299 ([M+H]⁺).

Preparation of N-((2-isopropyl-5-methoxyphenyl)carbamothioyl)benzamide(CA35)

The title compound was prepared as described in Example 68 using2-isopropyl-5-methoxyaniline (CA27) and isolated as a yellow liquid(4.63 g, 100%): ¹H NMR (400 MHz, CDCl₃) δ 12.23 (s, 1H), 9.13 (s, 1H),7.98-7.82 (m, 2H), 7.74-7.61 (m, 1H), 7.61-7.51 (m, 2H), 7.32-7.26 (m,2H), 6.89 (dd, J=8.7, 2.7 Hz, 1H), 3.81 (s, 3H), 3.10 (p, J=6.9 Hz, 1H),1.26 (d, J=6.8 Hz, 6H); ESIMS m/z 329 ([M+H]⁺).

Preparation of N-((2-ethyl-5-methylphenyl)carbamothioyl)benzamide (CA36)

The title compound was prepared as described in Example 68 using2-ethyl-5-methylaniline (CA28) and isolated as an orange solid (2.10 g,97%): mp 105-107° C.; ¹H NMR (400 MHz, CDCl₃) δ 12.18 (s, 1H), 9.14 (s,1H), 7.92 (dt, J=8.6, 1.7 Hz, 2H), 7.73-7.60 (m, 1H), 7.59-7.53 (m, 2H),7.50 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.11 (dd, J=7.8, 1.1 Hz, 1H),2.71-2.59 (m, 2H), 2.37 (s, 3H), 1.24 (t, J=7.6 Hz, 3H); ¹³C NMR (101MHz, CDCl₃) δ 179.72, 166.94, 136.22, 136.13, 135.53, 133.75, 131.65,129.23, 128.88, 128.86, 127.53, 127.23, 24.26, 20.98, 14.56; ESIMS m/z299 ([M+H]⁺).

Preparation of N-((2-ethyl-4-methylphenyl)carbamothioyl)benzamide (CA37)

The title compound was prepared as described in Example 68 using2-ethyl-4-methylaniline (CA29) and isolated as an orange solid (2.46 g,100%): mp 103° C. (dec.); ¹H NMR (400 MHz, CDCl₃) δ 12.16 (s, 1H), 9.18(s, 1H), 7.95-7.86 (m, 2H), 7.68-7.60 (m, 1H), 7.60-7.51 (m, 4H),7.15-7.05 (m, 2H), 2.66 (q, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.25 (t, J=7.6Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 179.89, 166.97, 138.94, 137.88,133.75, 133.20, 131.67, 129.77, 129.23, 127.55, 127.15, 126.71, 24.63,21.27, 14.52; ESIMS m/z 299 ([M+H]⁺).

Preparation of N-((5-chloro-2-isopropylphenyl)carbamothioyl)benzamide(CB31)

The title compound was prepared as described in Example 68 using5-chloro-2-isopropylaniline (CB27) followed by purification by flashcolumn chromatography and isolated as a light yellow solid (16.3 g,98%): ¹H NMR (400 MHz, DMSO-d₆) b 12.32 (s, 1H), 11.76 (s, 1H),8.07-7.95 (m, 2H), 7.72-7.63 (m, 1H), 7.60-7.50 (m, 3H), 7.42 (d, J=8.5Hz, 1H), 7.37 (dd, J=8.5, 2.2 Hz, 1H), 3.08 (hept, J=6.9 Hz, 1H), 1.19(d, J=6.8 Hz, 6H); ¹³C NMR (101 MHz, DMSO) δ 181.12, 168.37, 142.95,137.03, 133.18, 131.93, 129.67, 128.75, 128.40, 127.61, 127.55, 127.52,27.63, 22.84; ESIMS m/z 333 ([M+H]⁺).

Example 69: Preparation of 1-(5-methyl-2-propylphenyl)thiourea (CA38)

To N-((5-methyl-2-propylphenyl)carbamothioyl)benzamide (C72) (3.21 g,10.3 mmol) in methanol (80 mL) was added sodium hydroxide (2 N, 10.3 mL,20.5 mmol) and heated at 50° C. for 2 hours and then stirred at roomtemperature over the weekend. The reaction was concentrated, dilutedwith water, extracted with dichloromethane, filtered through a phaseseparator, concentrated, and dried in a vacuum oven to provide the titlecompound as a tan solid (1.80 g, 83%): mp 143-145° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.84 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.12 (dd, J=7.8, 1.2 Hz,1H), 7.04 (s, 1H), 5.99 (d, J=254.5 Hz, 2H), 2.57 (d, J=7.5 Hz, 2H),2.33 (s, 3H), 1.59 (dq, J=14.8, 7.4 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H); ¹³CNMR (101 MHz, CDCl₃) δ 181.96, 137.53, 136.74, 134.00, 130.69, 129.72,127.85, 32.90, 23.66, 20.80, 13.93; ESIMS m/z 209 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 69.

Preparation of 1-(2-ethyl-6-methylphenyl)thiourea (CA39)

The title compound was prepared as described in Example 69 usingN-((2-ethyl-6-methylphenyl)carbamothioyl)benzamide (CA34), furtherpurified by trituration with water and isolated as a white solid (3.46g, 83%): ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.25 (d, J=7.9 Hz, 1H),7.22-7.11 (m, 2H), 6.13 (bs, 1H), 5.33 (bs, 1H), 2.77-2.55 (m, 2H), 2.31(s, 3H), 1.21 (t, J=7.6 Hz, 3H); ESIMS m/z 195 ([M+H]⁺).

Preparation of 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40)

The title compound was prepared as described in Example 69 usingN-((2-isopropyl-5-methoxyphenyl)carbamothioyl)benzamide (CA35) andisolated as an orange solid (2.65 g, 83%): mp 134-139° C.; ¹H NMR (400MHz, CDCl₃) δ 7.60 (s, 1H), 7.30 (d, J=8.7 Hz, 1H), 6.93 (dd, J=8.7, 2.7Hz, 1H), 6.75 (d, J=2.7 Hz, 1H), 5.88 (s, 2H), 3.79 (s, 3H), 3.10 (p,J=6.9 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H); ESIMS m/z 225 ([M+H]⁺).

Preparation of 1-(2-ethyl-5-methylphenyl)thiourea (CA41)

The title compound was prepared as described in Example 69 usingN-((2-ethyl-5-methylphenyl)carbamothioyl)benzamide (CA36) and isolatedas a pale orange solid (1.26 g, 94%): mp 143-147° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.48 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H),7.04 (s, 1H), 5.86 (s, 2H), 2.61 (q, J=7.5 Hz, 2H), 2.33 (s, 3H), 1.19(t, J=7.6 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 182.13, 138.27, 137.53,133.74, 129.95, 129.93, 127.84, 24.00, 20.79, 14.77; ESIMS m/z 195([M+H]⁺).

Preparation of 1-(2-ethyl-4-methylphenyl)thiourea (CA42)

The title compound was prepared as described in Example 69 usingN-((2-ethyl-4-methylphenyl)carbamothioyl)benzamide (CA37) and isolatedas a tan solid (1.40 g, 86%): mp 153-155° C.; ¹H NMR (400 MHz, CDCl₃) δ7.60 (s, 1H), 7.14 (d, J=0.5 Hz, 1H), 7.08 (dt, J=8.1, 4.8 Hz, 2H), 5.85(d, J=184.3 Hz, 2H), 2.62 (q, J=7.6 Hz, 2H), 2.35 (s, 3H), 1.20 (t,J=7.6 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 182.32, 141.33, 139.33,131.29, 130.75, 128.15, 127.36, 24.36, 21.18, 14.74; ESIMS m/z 195([M+H]⁺).

Preparation of 1-(5-chloro-2-isopropylphenyl)thiourea (CB32)

The title compound was prepared as described in Example 69 usingN-((5-chloro-2-isopropylphenyl)carbamothioyl)benzamide (CB31) andisolated as a brown sticky gum (1.38 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ7.96 (s, 1H), 7.34 (d, J=1.4 Hz, 2H), 7.24 (t, J=1.3 Hz, 1H), 5.97 (s,2H), 3.27-3.10 (m, 1H), 1.21 (d, J=6.8 Hz, 6H); ESIMS m/z 229 ([M+H]⁺).

Example 70: Preparation of 4-methoxy-2-nitro-1-(prop-1-en-2-yl)benzene(CA43)

To 1-chloro-4-methoxy-2-nitrobenzene (5.03 g, 26.8 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.41 g, 32.2mmol), bis(triphenylphosphine)palladium(II) chloride (1.50 g, 2.15mmol), and sodium carbonate (3.41 g, 32.2 mmol) was added dioxane/water(4:1, 100 mL:25 mL). The reaction was heated at 80° C. for 5 hours. Thereaction was cooled to room temperature overnight. The reaction mixturewas diluted with water, extracted with ethyl acetate (3×), dried oversodium sulfate, filtered, and concentrated. Purification by flash columnchromatography using 0-5% ethyl acetate/hexanes as eluent followed bydrying in vacuum oven provided the title compound as an orange oil (2.74g, 53%): ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J=2.7 Hz, 1H), 7.23 (d,J=8.6 Hz, 1H), 7.08 (dd, J=8.5, 2.6 Hz, 1H), 5.24-4.75 (m, 2H), 3.86 (s,3H), 2.19-1.88 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 158.79, 148.61,142.53, 131.41, 131.32, 119.24, 115.20, 108.64, 55.84, 23.38; EIMS m/z193 ([M]⁺).

The following compounds were prepared in accordance to the procedure inExample 70.

Preparation of 4-chloro-2-nitro-1-(prop-1-en-2-yl)benzene (CB33)

The title compound was prepared as described in Example 70 using1-bromo-4-chloro-2-nitrobenzene heated overnight and isolated as a lightorange liquid (10.73 g, 84%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=2.2Hz, 1H), 7.76 (dd, J=8.3, 2.2 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 5.24 (p,J=1.5 Hz, 1H), 4.95 (p, J=1.0 Hz, 1H), 2.07 (dd, J=1.5, 0.9 Hz, 3H); ¹³CNMR (101 MHz, DMSO) b 148.37, 140.83, 136.10, 132.62, 132.45, 131.63,123.50, 115.98, 22.60; EIMS m/z 197 ([M]⁺).

Example 71: Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC2)

A fine suspension of(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) (0.300 g, 0.897 mmol) in dichloromethane (4.0 mL) was added, in aslow dropwise fashion, to a biphasic solution of bis(trichloromethyl)carbonate (0.107 g, 0.359 mmol) and sodium acetate (0.221 g, 2.69 mmol)in dichloromethane (4.0 mL) and water (2.0 mL). The reaction was allowedto stir for 30 minutes. The reaction was passed through a phaseseparator, washing with additional dichloromethane and the organic layerwas concentrated. The resulting residue was diluted with acetonitrile(4.0 mL), and 1-(2-ethylphenyl)thiourea (0.178 g, 0.987 mmol) and cesiumcarbonate (0.351 g, 1.08 mmol) were added as solids. The reaction wasallowed to stir at room temperature overnight. The reaction mixture wasdiluted with dichloromethane and water and passed through a phaseseparator. The organic layer was concentrated on to Celite® and purifiedby reverse phase flash column chromatography (C₁₈) using 20-100%acetonitrile/water as eluent providing the title compound as a whitesolid (0.100 g, 16%) contaminated with ˜20% of the dimer urea: ¹H NMR(400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 10.24 (s, 1H), 9.41 (s, 1H), 9.40(d, J=1.0 Hz, 1H), 8.18-8.03 (m, 6H), 7.63 (dddd, J=9.2, 4.3, 2.0, 1.0Hz, 3H), 7.54 (ddd, J=12.1, 7.0, 4.8 Hz, 2H), 7.50-7.38 (m, 3H),7.35-7.26 (m, 1H), 7.26-7.20 (m, 2H), 4.44 (d, J=5.8 Hz, 2H), 2.56 (q,J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.96; ESIMS m/z 541 ([M+H]⁺), 539 ([M−H]⁻)

The following compounds were prepared in accordance to the procedure inExample 71.

Preparation of1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC3)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as a whitesolid (0.157 g, 30%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 10.26(s, 1H), 9.41 (s, 1H), 8.15-8.03 (m, 4H), 7.63 (ddt, J=7.8, 1.9, 0.9 Hz,2H), 7.58-7.44 (m, 3H), 7.39 (dd, J=8.8, 5.6 Hz, 1H), 7.17 (dd, J=10.3,3.0 Hz, 1H), 7.05 (td, J=8.5, 3.0 Hz, 1H), 4.44 (d, J=5.8 Hz, 2H),3.05-2.93 (m, 1H), 1.16 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.96, −114.33; ESIMS m/z 573 ([M+H]⁺), 571 ([M−H]⁻).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC5)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as a whitesolid (0.110 g, 21%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.21(s, 1H), 9.41 (s, 1H), 8.17-8.05 (m, 4H), 7.63 (dq, J=8.9, 0.9 Hz, 2H),7.56-7.44 (m, 3H), 7.26 (d, J=8.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H),7.06-6.98 (m, 1H), 4.44 (d, J=5.8 Hz, 2H), 2.97 (hept, J=6.7 Hz, 1H),2.31 (s, 3H), 1.16 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.96; ESIMS m/z 569 ([M+H]⁺), 567 ([M−H]⁻).

Preparation of1-[(2-ethyl-5-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC7)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) and 1-(2-ethyl-5-methylphenyl)thiourea (CA41) and isolated as anoff white solid (0.092 g, 18%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s,1H), 10.22 (s, 1H), 9.41 (d, J=0.8 Hz, 1H), 8.18-8.04 (m, 4H), 7.63 (d,J=8.7 Hz, 2H), 7.57-7.44 (m, 3H), 7.39-7.31 (m, 1H), 7.17 (d, J=7.7 Hz,1H), 7.04 (dd, J=8.0, 1.7 Hz, 1H), 4.44 (d, J=5.8 Hz, 2H), 2.51 (dt,J=3.6, 1.9 Hz, 2H), 2.27 (s, 3H), 1.14-1.08 (m, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −56.96; ESIMS m/z 555 ([M+H]⁺), 553 ([M−H]⁻).

Preparation of1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC8)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) and 1-(5-methyl-2-propylphenyl)thiourea (CA38) and isolated as anoff white solid (0.079 g, 15%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s,1H), 10.22 (s, 1H), 9.41 (s, 1H), 8.14-8.06 (m, 4H), 7.69-7.61 (m, 2H),7.56-7.44 (m, 3H), 7.39 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.08-6.99 (m,1H), 4.44 (d, J=5.8 Hz, 2H), 2.49-2.43 (m, 2H), 2.27 (s, 3H), 1.50 (h,J=7.3 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.96; ESIMS m/z 569 ([M+H]⁺), 567 ([M−H]⁻).

Preparation of1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC6)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as a whitesolid (0.076 g, 15%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.18(s, 1H), 9.41 (s, 1H), 8.11-8.04 (m, 5H), 7.69-7.58 (m, 3H), 7.58-7.35(m, 5H), 6.90-6.82 (m, 1H), 6.77 (dd, J=8.7, 2.9 Hz, 1H), 4.43 (d, J=5.8Hz, 2H), 3.75 (s, 3H), 2.18 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.96; ESMIS m/z 557 ([M+H]⁺), 555 ([M−H]⁻).

Preparation of1-(o-tolylcarbamothioyl)-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC1)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(C16) and 1-(o-tolyl)thiourea and isolated as a white solid (0.116 g,24%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H), 10.22 (s, 1H), 9.41 (s,1H), 8.18-8.06 (m, 4H), 7.64 (dp, J=7.8, 0.9 Hz, 3H), 7.55 (t, J=5.9 Hz,1H), 7.52-7.46 (m, 2H), 7.32-7.28 (m, 1H), 7.27-7.17 (m, 2H), 4.46 (d,J=5.8 Hz, 2H), 2.25 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMSm/z 527 ([M+H]⁺), 525 ([M−H]⁻).

Preparation of1-[(2-isopropylphenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC14)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(CA3) and 1-(2-isopropylphenyl)thiourea and isolated as a white solid(0.088 g, 17%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 10.24 (s,1H), 9.55 (s, 1H), 8.22 (d, J=8.5 Hz, 2H), 8.19-8.13 (m, 2H), 8.01 (d,J=8.4 Hz, 2H), 7.56 (t, J=5.9 Hz, 1H), 7.53-7.48 (m, 2H), 7.45 (dd,J=7.8, 1.5 Hz, 1H), 7.38 (dd, J=7.7, 1.6 Hz, 1H), 7.30 (td, J=7.5, 1.5Hz, 1H), 7.24 (td, J=7.6, 1.7 Hz, 1H), 4.47 (d, J=5.8 Hz, 2H), 3.05(hept, J=7.0 Hz, 1H), 1.20 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆)δ −60.79; ESIMS m/z 539 ([M+H]⁺), 537 ([M−H]⁻).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC15)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(CA3) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as a whitesolid (0.073 g, 14%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 10.21(s, 1H), 9.55 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.19-8.12 (m, 2H), 8.01(d, J=8.5 Hz, 2H), 7.54 (t, J=6.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.29 (d,J=8.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.07-7.01 (m, 1H), 4.47 (d, J=5.8Hz, 2H), 3.00 (hept, J=6.9 Hz, 1H), 2.33 (s, 3H), 1.19 (d, J=6.8 Hz,6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.79; ESIMS m/z 553 ([M+H]⁺), 551([M−H]⁻).

Preparation of1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC16)

The title compound was prepared as described in Example 71 using(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine(CA3) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as a whitesolid (0.033 g, 6%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 9.53 (s,1H), 9.18 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.15-8.06 (m, 2H), 8.01 (d,J=8.5 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.6 Hz, 1H), 7.07 (t,J=6.0 Hz, 1H), 6.92 (d, J=2.9 Hz, 1H), 6.88 (dd, J=8.6, 2.9 Hz, 1H),4.29 (dd, J=5.9, 2.9 Hz, 2H), 3.82 (s, 3H), 2.11 (s, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −60.79; ESIMS m/z 541 ([M+H]⁺), 539 ([M−H]⁻).

Example 72: Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P3, P1172)

To a 20 mL vial was added1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC3) (0.092 g, 0.16 mmol), sodium acetate (0.040 g, 0.48 mmol), methyl2-bromoacetate (0.084 mL, 0.80 mmol) and acetonitrile (2.0 mL). The vialwas sealed and the reaction was heated overnight at 65° C. The reactionmixture was diluted with brine solution and dichloromethane and passedthrough a phase separator. The organic layer was concentrated and theresulting residue was purified by flash column chromatography using10-80% ethyl acetate/hexanes as eluent providing the title compound as awhite solid (0.058 g, 58%).

The following compounds were prepared in accordance to the procedure inExample 72.

Preparation of(Z)-1-(3-(2-ethyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P7)

The title compound was prepared as described in Example 72 using1-[(2-ethyl-5-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC7) and isolated as an off-white solid (0.034 g, 44%).

Preparation of(Z)-1-(3-(5-methyl-2-propylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P8, P852)

The title compound was prepared as described in Example 72 using1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC8) and isolated as an off-white solid (0.018 g, 25%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P6)

The title compound was prepared as described in Example 72 using1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC6) and isolated as an off-white solid (0.041 g, 46%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P5)

The title compound was prepared as described in Example 72 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC5) and isolated as an off-white solid (0.012 g, 25%).

Preparation of(Z)-1-(3-(2-ethylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P2, P532)

The title compound was prepared as described in Example 72 using1-[(2-ethylphenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC2) and isolated as a white solid (0.031 g, 28%).

Preparation of(Z)-1-(4-oxo-3-(o-tolyl)thiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P1)

The title compound was prepared as described in Example 72 using1-(o-tolylcarbamothioyl)-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC1) and ethanol as solvent and isolated as a white solid (0.086 g,79%).

Preparation of(Z)-1-(3-(2-isopropylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P14)

The title compound was prepared as described in Example 72 using1-[(2-isopropylphenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC14) and ethanol as solvent and isolated as a white solid (0.055 g,69%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P15)

The title compound was prepared as described in Example 72 using1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC15) and ethanol as solvent and isolated as a white solid (0.049 g,80%).

Example 73: Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-methylthiazol-2(3H)-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)urea(P20)

To a 20 mL vial was added1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(PC5) (0.044 g, 0.077 mmol), sodium acetate (0.019 g, 0.23 mmol),1-chloropropan-2-one (0.0092 mL, 0.12 mmol) and acetonitrile (1.5 mL).The vial was sealed and heated overnight at 65° C. The reaction mixturewas diluted with brine solution and dichloromethane and passed through aphase separator. The organic layer was concentrated and the resultingresidue was purified by flash column chromatography using 10-80% ethylacetate/hexanes as eluent providing the title compound as an off-whitesolid (0.010 g, 21%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H),8.14-8.01 (m, 4H), 7.70 (s, 1H), 7.62 (dq, J=7.7, 1.0 Hz, 2H), 7.45-7.35(m, 2H), 7.34-7.27 (m, 1H), 7.15 (t, J=1.3 Hz, 2H), 6.66 (q, J=0.9 Hz,1H), 4.47-4.28 (m, 2H), 2.73-2.62 (m, 1H), 2.39 (s, 3H), 2.10 (d, J=1.1Hz, 3H), 1.10 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −56.96; ESIMS m/z 607 ([M+H]⁺).

Example 74: Preparation of3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44)

To a suspension of3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CA13) (3.0 g, 8.0 mmol) and triethylamine (1.1 mL, 8.0 mmol) intoluene (80 mL) in a 200 mL round bottomed flask was added diphenylphosphorazidate (1.7 mL, 8.0 mmol). The reaction mixture was stirred atroom temperature for 2 hours. The reaction mixture was concentrated onto Celite®. Purification by flash column chromatography using 0-50%ethyl acetate/hexanes as eluent provided a pale yellow oil (1.8 g) whichwas stored overnight. The oil, which was determined by ¹H NMR to be amixture of acyl azide and isocyanate solidified over time and was storedan additional night under vacuum. The resultant solid was dissolved in1,2-dichloroethane (50 mL) 1,2-dichloroethane and heated at 60° C. for 3hours. The solvent was concentrated to give the title compound (1.8 g,59%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.13-8.06 (m, 2H),8.06-7.98 (m, 2H), 7.63 (dq, J=7.9, 1.0 Hz, 2H), 7.49 (td, J=7.6, 0.6Hz, 1H), 7.41 (dt, J=7.7, 1.3 Hz, 1H), 3.66 (t, J=6.6 Hz, 2H), 2.99 (t,J=6.7 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97.

The following compounds were prepared in accordance to the procedure inExample 74.

Preparation of3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34)

The title compound was prepared as described in Example 74 using2-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)aceticacid (CB23) and isolated as a white solid (2.41 g, 48%, 85% pure): ¹HNMR (400 MHz, DMSO-d₆) b 9.43 (s, 1H), 8.17-8.03 (m, 4H), 7.65-7.44 (m,4H), 4.73 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −57.00; ESIMS m/z 361([M+H]⁺).

Example 75: Preparation of1-(o-tolylcarbamothioyl)-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC74)

To a 20 mL vial, 1-(o-tolyl)thiourea (0.096 g, 0.58 mmol) and cesiumcarbonate (0.22 g, 0.68 mmol) were charged as solids. Then3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) (0.20 g, 0.52 mmol) in acetonitrile (4.0 mL) was added. Thereaction was allowed to stir at room temperature overnight. The reactionmixture was diluted with dichloromethane and filtered through a phaseseparator. The filtrate was purified by flash column chromatographyusing 0-50% ethyl acetate/hexanes as eluent followed by flash columnchromatography using 10-50% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent to provide the title compound as awhite solid (0.11 g, 37%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H),10.12 (s, 1H), 9.42 (s, 1H), 8.13-8.05 (m, 2H), 8.04-7.96 (m, 2H),7.66-7.54 (m, 3H), 7.54-7.46 (m, 1H), 7.39 (dt, J=7.7, 1.5 Hz, 1H),7.29-7.24 (m, 1H), 7.24-7.14 (m, 2H), 7.03 (t, J=5.6 Hz, 1H), 3.46 (q,J=6.6 Hz, 2H), 2.96-2.84 (m, 2H), 2.20 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −56.96; ESIMS m/z 541 ([M+H]⁺), 539 ([M−H]⁻).

The following compounds were prepared in accordance to the procedure inExample 75.

Preparation of1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC87)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(4-methoxy-2-methylphenyl)thiourea isolated as a whitesolid (0.105 g, 34%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 10.07(s, 1H), 9.42 (s, 1H), 8.13-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.66-7.57(m, 2H), 7.53-7.45 (m, 1H), 7.42-7.32 (m, 2H), 7.01 (t, J=5.7 Hz, 1H),6.85-6.81 (m, 1H), 6.76 (dd, J=8.7, 2.9 Hz, 1H), 3.74 (s, 3H), 3.45 (q,J=6.6 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.15 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −56.97; ESIMS m/z 517 ([M+H]⁺), 569 [(M−H)⁺].

Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC75)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(2-ethylphenyl)thiourea isolated as a white solid (0.104 g,35%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 10.13 (s, 1H), 9.42 (s,1H), 8.15-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.67-7.57 (m, 2H), 7.56-7.45(m, 2H), 7.39 (dt, J=7.7, 1.4 Hz, 1H), 7.33-7.25 (m, 1H), 7.25-7.17 (m,2H), 7.09-6.96 (m, 1H), 3.47 (q, J=6.5 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H),2.58-2.51 (m, 2H), 1.11 (t, J=7.5 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.97; ESIMS m/z 555 ([M+H]⁺), 553 ([M−H]⁻).

Preparation of1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC83)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) isolated as a whitesolid (0.137 g, 45%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 10.13(s, 1H), 9.42 (s, 1H), 8.16-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.62 (ddd,J=7.9, 2.0, 1.0 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.4Hz, 1H), 7.21-7.12 (m, 1H), 7.13-7.05 (m, 2H), 7.00 (t, J=5.7 Hz, 1H),3.47 (q, J=6.7 Hz, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.47 (dd, J=7.6, 2.9 Hz,2H), 2.14 (s, 3H), 1.14-1.08 (m, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.97; ESIMS m/z 569 ([M+H]⁺), 567 ([M−H]⁻).

Preparation of1-[(2-isopropylphenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC76)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(2-isopropylphenyl)thiourea isolated as a white solid(0.033 g, 11%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.14 (s,1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.94 (m, 2H), 7.68-7.57 (m,2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dq, J=7.8, 1.5 Hz, 2H), 7.34 (dd,J=7.8, 1.6 Hz, 1H), 7.26 (td, J=7.5, 1.5 Hz, 1H), 7.20 (td, J=7.5, 1.6Hz, 1H), 7.03 (t, J=5.7 Hz, 1H), 3.47 (q, J=6.6 Hz, 2H), 2.98 (p, J=6.9Hz, 1H), 2.89 (t, J=6.9 Hz, 2H), 1.15 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −56.96; ESIMS m/z 569 ([M+H]⁺), 567 ([M−H]⁻).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC84)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(2-isopropyl-4-methylphenyl)thiourea isolated as a whitesolid (0.077 g, 25%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 10.10(s, 1H), 9.42 (s, 1H), 8.15-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.61 (ddd,J=7.9, 2.0, 1.0 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.4Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.16-7.11 (m, 1H), 7.05-6.96 (m, 2H),3.46 (q, J=6.7 Hz, 2H), 2.91 (dt, J=17.9, 6.9 Hz, 3H), 2.30 (s, 3H),1.14 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.97; ESIMS m/z583 ([M+H]⁺), 581 ([M−H]⁻).

Preparation of1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC85)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(4-fluoro-2-isopropylphenyl)thiourea isolated as a whitesolid (0.085 g, 27%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.17(s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.95 (m, 2H), 7.68-7.58(m, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.43-7.31 (m, 2H), 7.15 (dd, J=10.3,3.0 Hz, 1H), 7.03 (td, J=8.3, 2.9 Hz, 2H), 3.47 (q, J=6.6 Hz, 2H),3.01-2.82 (m, 3H), 1.14 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.97, −114.40; ESIMS m/z 587 ([M+H]⁺), 585 ([M−H]⁻).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC81)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(2-isopropyl-5-methylphenyl)thiourea isolated as anoff-white solid (0.019 g, 6%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s,1H), 10.12 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.96 (m, 2H),7.62 (ddd, J=7.8, 1.9, 0.9 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt,J=7.7, 1.5 Hz, 1H), 7.24-7.17 (m, 2H), 7.12-7.05 (m, 1H), 7.02 (t, J=5.8Hz, 1H), 3.52-3.42 (m, 2H), 2.91 (dt, J=14.1, 6.9 Hz, 3H), 2.25 (s, 3H),1.13 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z583 ([M+H]⁺), 581 ([M−H]⁻).

Preparation of1-[(5-methyl-2-propyl-phenyl)carbamothioyl]-3-[2-[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]ethyl]urea(PC80)

The title compound was prepared as described in Example 75 using3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CA44) and 1-(5-methyl-2-propylphenyl)thiourea (CA38) isolated as awhite solid (0.107 g, 34%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1H),10.09 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.95 (m, 2H), 7.61(dd, J=8.6, 1.3 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.44-7.34 (m, 2H), 7.13(d, J=7.8 Hz, 1H), 7.07-6.97 (m, 2H), 3.46 (q, J=6.5 Hz, 2H), 2.89 (t,J=6.9 Hz, 2H), 2.48-2.39 (m, 2H), 2.26 (s, 3H), 1.54-1.42 (m, 2H), 0.84(t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −56.96; ESIMS m/z 583([M+H]⁺), 581 ([M−H]⁻).

Preparation of1-(o-tolylcarbamothioyl)-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB18)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(o-tolyl)thiourea and isolated as an off-white solid (0.148g, 37%).

Preparation of1-[(4-methoxy-2-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB19)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as anoff-white solid (0.212 g, 50%).

Preparation of1-[(2-ethylphenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB20)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(2-ethylphenyl)thiourea and isolated as an off-white solid(0.152 g, 37%).

Preparation of1-[(2-ethyl-6-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB21)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) and isolated as anoff-white solid (0.212 g, 50%).

Preparation of1-[(2-isopropylphenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB22)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(2-isopropylphenyl)thiourea and isolated as an off-whitesolid (0.213 g, 47%).

Preparation of1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB23)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as anoff-white solid (0.216 g, 50%).

Preparation of1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB24)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as anoff-white solid (0.242 g, 56%).

Preparation of1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB25)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as anoff-white solid (0.181 g, 42%).

Preparation of1-[(5-chloro-2-isopropyl-phenyl)carbamothioyl]-3-[[3-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea(FB26)

The title compound was prepared as described in Example 75 using3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB34) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) and isolated asan off-white solid (0.170 g, 38%).

Example 76: Preparation of3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-ol(CA45)

In a 500 mL round bottomed flask3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoicacid (CA13) (5.68 g, 15.1 mmol) was dissolved in tetrahydrofuran (151mL). The reaction was cooled in an ice water bath and placed under inertatmosphere. Aluminum(III) lithium hydride (2.0 M in tetrahydrofuran,15.8 mL, 31.6 mmol) was added dropwise. The reaction was allowed togradually warm to room temperature and stir overnight. The reaction wascooled in an ice bath and water (1.2 mL) was added dropwise to quenchexcess aluminum(III) lithium hydride, the reaction mixture was allowedto stir for 1 hour. Then sodium hydroxide (15 wt %, 1.2 mL) was addeddropwise. The reaction was allowed to stir for 1 hour. Then water (3.6mL) was added. The resulting precipitate was removed via filtration. Thefiltrate was concentrated to give a yellow solid (5.20 g). The solid waspurified by flash column chromatography using 0-60% ethylacetate/hexanes as eluent providing the title compound as a white solid(4.01 g, 72%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.18-8.04 (m,2H), 7.99-7.89 (m, 2H), 7.68-7.57 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.32(dt, J=7.7, 1.5 Hz, 1H), 4.51 (t, J=5.2 Hz, 1H), 3.45 (td, J=6.4, 5.1Hz, 2H), 2.71 (dd, J=8.8, 6.7 Hz, 2H), 1.87-1.70 (m, 2H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −56.97; ESIMS m/z 364 ([M+H]⁺).

Example 77: Preparation of 1-bromo-3-(but-3-en-1-yl)benzene (CA46)

To a solution of 1-bromo-3-(bromomethyl)benzene (10.0 g, 40.0 mmol) intetrahydrofuran (50 mL), under an inert atmosphere was addedallylmagnesium bromide (1.0 M in diethyl ether, 40.0 mL, 40.0 mmol). Thereaction was allowed to reflux overnight. The reaction was quenched withsulfuric acid (2 M, 45 mL). The resulting biphasic solution was solutionwas partitioned. The aqueous layer was extracted with diethyl ether(2×50 mL). The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated. The resulting residue was purifiedby flash column chromatography using 100% hexanes as eluent providingthe title compound as a clear liquid (7.51 g, 71%, ˜80% pure): ¹H NMR(400 MHz, DMSO-d₆) δ 7.42 (ddd, J=2.1, 1.4, 0.7 Hz, 1H), 7.37 (dt,J=7.1, 2.1 Hz, 1H), 7.28-7.18 (m, 2H), 5.81 (ddt, J=16.9, 10.2, 6.5 Hz,1H), 5.09-4.90 (m, 2H), 2.67 (dd, J=8.6, 6.8 Hz, 2H), 2.32 (tdt, J=7.7,6.5, 1.5 Hz, 2H); 13C NMR (101 MHz, DMSO-d₆) δ 144.35, 137.61, 131.05,130.28, 128.62, 127.44, 121.53, 115.37, 34.59, 33.91; EIMS m/z 210([M]⁺).

Example 78: Preparation of 4-(3-bromophenyl)butan-1-ol (CA47)

To a solution of 1-bromo-3-(but-3-en-1-yl)benzene (CA46) (7.51 g, 35.6mmol) in hexanes (80 mL) was added (1S,5S)-9-borabicyclo[3.3.1]nonane(0.5 M in tetrahydrofuran, 74.7 mL, 37.4 mmol). The reaction was allowedto stir at room temperature overnight. To the resulting clear solutionsodium hydroxide (6.0 M, 5.93 mL, 35.6 mmol) was added dropwise. Thereaction was placed in an ice water bath and hydrogen peroxide (13.8 mL,135 mmol) was added. The resulting mixture was then heated to aninternal temperature of 50° C. for overnight. The reaction mixture wascooled to room temperature. The biphasic solution was partitioned, andthe organic layer was washed with sodium bisulfite, and brine solution.The combined aqueous layers were made basic with saturated sodiumcarbonate, and extracted with diethyl ether (2×100 mL). The combinedorganics were dried over magnesium sulfate, filtered, and concentrated.The liquid was loaded on to silica and purified by flash columnchromatography using 0-40% ethyl acetate/hexanes as eluent providing thetitle compound as a clear liquid (7.50 g, 90%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.40 (t, J=1.9 Hz, 1H), 7.37 (dt, J=7.6, 1.8 Hz, 1H),7.28-7.17 (m, 2H), 4.39 (t, J=5.2 Hz, 1H), 3.40 (td, J=6.5, 5.2 Hz, 2H),2.57 (t, J=7.6 Hz, 2H), 1.65-1.51 (m, 2H), 1.49-1.35 (m, 2H); EIMS m/z228 ([M]⁺).

Example 79: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-methylthiazol-2(3H)-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P65)

ToN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) (0.23 g, 0.40 mmol) in butanone (4 mL) was addedtriethylamine (0.060 mL, 0.43 mmol) and chloroacetone (0.035 mL, 0.44mmol) and heated at 80° C. overnight. The reaction was cooled, dilutedwith water, extracted dichloromethane (2×), and filtered through a phaseseparator. The organic layer was concentrated and loaded onto Celite®cartridge with dichloromethane. Purification by flash columnchromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes as eluent, followed by drying in a vacuum ovenprovided the title compound as an orange solid (0.085 g, 34%).

The following compounds were prepared in accordance to the procedure inExample 79.

Preparation of(Z)-1-(4-hydroxy-3-(2-isopropyl-5-methylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB67)

The title compound was prepared as described in Example 79 usingN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) and sodium acetate as base at room temperature; purified byreverse-phase flash column chromatography using 0-100%acetonitrile/water as eluent and isolated as a clear oil (0.036 g, 33%).

Example 80: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-1,3-thiazinan-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P59)

ToN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) (181 mg, 0.31 mmol) and potassium carbonate (0.064 g, 0.47mmol) in butanone (3.1 mL) was added 1-bromo-3-chloropropane (0.050 mL,0.47 mmol). The reaction was heated at 60° C. overnight. The reactionmixture was cooled, diluted with water, extracted with dichloromethane(2×), and filtered through a phase separator. The organic layer wasconcentrated and loaded onto a Celite® cartridge with dichloromethane.Purification by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes as eluent, followed byreverse-phase flash column chromatography using 0-100%acetonitrile/water as eluent and drying in a vacuum oven provided thetitle compound as a white solid (0.032 g, 16%).

The following compounds were prepared in accordance to the procedure inExample 80.

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P58)

The title compound was prepared as described in Example 80 usingN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) and 1,2-dibromopropane at 80° C. and isolated as a yellowoil (0.050 g, 26%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-5-methyl-1,3-thiazinan-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(P64)

The title compound was prepared as described in Example 80 usingN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) and 1-bromo-3-chloro-2-methylpropane and isolated as awhite solid (0.061 g, 14%).

Example 80a: Preparation of(Z)-1-(3-(2-ethyl-5-methylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB55)

3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) (0.16 g, 0.42 mmol), 1-(2-ethyl-5-methylphenyl)thiourea (CA41)(0.081 g, 0.42 mmol), and cesium carbonate (0.13 g, 0.39 mmol) inacetonitrile (1.9 mL) was stirred at room temperature for 3 hours. Thereaction was diluted with butanone (2 mL) and potassium carbonate (0.12g, 0.83 mmol) and 1,2-dibromopropane (0.090 mL, 0.83 mmol) were added.The reaction was heated to 60° C. for 6 hours. The reaction was dilutedwith water and extracted with dichloromethane (2×) and the organiclayers were filtered through a phase separator and concentrated.Purification by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided thetitle compound as a yellow oil (0.034 g, 13%).

The following compounds were prepared in accordance to the procedure inExample 80a.

Preparation of(Z)-1-(3-(2-ethyl-4-methylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB56)

The title compound was prepared as described in Example 80a using3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and 1-(2-ethyl-4-methylphenyl)thiourea (CA42) isolated as ayellow oil (0.040 g, 16%).

Preparation of(Z)-1-(3-(4-fluoro-2-isopropylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB57)

The title compound was prepared as described in Example 80a using3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as ayellow oil (0.056 g, 22%).

Preparation of(Z)-1-(3-(4-methoxy-2-methylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB58)

The title compound was prepared as described in Example 80a using3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as a yellowoil (0.054 g, 21%).

Preparation of(Z)-1-(3-(2,6-dimethylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB59)

The title compound was prepared as described in Example 80a using3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and 1-(2,6-dimethylphenyl)thiourea and isolated as a clear oil(0.044 g, 18%).

Preparation of(Z)-1-(3-(2-isopropyl-4-methylphenyl)-4-methylthiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB60)

The title compound was prepared as described in Example 80a using3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as ayellow foam (0.047 g, 17%).

Example 81: Preparation of ethyl3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoate(CA48)

Sodium hydride (60% immersion in oil, 0.32 g, 7.9 mmol) was weighed intoan oven-dried three neck round bottomed flask. The flask was placedunder nitrogen and tetrahydrofuran (44 mL) was added. The stirringmixture was placed in an ice bath. Triethylphosphonoacetate (1.4 mL, 6.9mmol) was added and the mixture was stirred for 2 hours. Added1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-one(CA7) (2.4 g, 6.5 mmol) as a solid and warmed to room temperatureovernight. The reaction was diluted with water and extracted with ethylacetate/hexanes (1:1, 2×). The organic layers were dried over sodiumsulfate, filtered, and concentrated. To the crude residue was addedpalladium on carbon (10 wt %, 0.70 g, 0.66 mmol) and dissolved in ethylacetate (20 mL). The reaction was stirred under hydrogen by balloonovernight. The reaction mixture was filtered through Celite® andconcentrated to give the title compound as a brown liquid (2.7 g, 90%):¹H NMR (400 MHz, CDCl₃) δ 8.55 (d, J=0.6 Hz, 1H), 8.11 (dd, J=8.1, 6.0Hz, 2H), 7.83-7.76 (m, 2H), 7.38 (dq, J=7.9, 1.0 Hz, 2H), 7.35-7.27 (m,2H), 4.24-4.14 (m, 1H), 4.04 (qd, J=7.1, 1.6 Hz, 1H), 3.13-2.99 (m, 1H),2.74-2.55 (m, 2H), 1.79-1.61 (m, 2H), 1.38-1.24 (m, 3H), 1.06 (dt,J=72.0, 7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 434([M+H]⁺).

Example 82: Preparation of para-toluenesulfonic acid salt of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5A)

To(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5) (4.82 g, 7.46 mmol) in a 250 mL round bottomed flask was addedisopropanol (50 mL). The suspension was warmed to 50° C. and stirred for20 minutes. Acetone (50 mL) was added. 4-Methylbenzenesulfonic acidhydrate (1.42 g, 7.46 mmol) dissolved in acetone (20 mL) and added tothe above solution in a dropwise manner. The resulting clear light brownsolution was concentrated at 50° C. The resultant residue was dried in avacuum oven at 50° C. overnight. The brown foam was transferred to a 500mL round bottomed flask and dissolved in acetone (200 mL). The mixturewas heated to reflux for 15 hours. The solution was concentratedproviding the title compound as a dark gray foam (5.90 g, 95%).

Example 83: Preparation of2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (CA49)

Method A.

To (1-(2-isopropyl-5-methylphenyl)thiourea (0.20 g, 0.96 mmol) inethanol (8.0 mL) was added methyl bromoacetate (0.17 mL, 1.9 mmol) andsodium acetate (0.23 g, 2.8 mmol). The reaction was stirred overnight atroom temperature. The solution was poured onto water and extracted withethyl acetate (3×) and the organics were dried and concentrated to givethe title compound as a red solid (0.24 g, 93%): ¹H NMR (400 MHz, CDCl₃)δ 7.21 (d, J=7.9 Hz, 1H), 7.07 (dd, J=8.3, 1.8 Hz, 1H), 6.85 (d, J=1.6Hz, 1H), 3.85 (d, J=0.9 Hz, 2H), 3.03 (p, J=6.9 Hz, 1H), 2.31 (t, J=0.7Hz, 4H), 1.15 (d, J=6.9 Hz, 6H); ESIMS m/z 248 ([M]⁺).

Method B, Step 1.

2-Isopropyl-5-methylaniline (286 g, 1.91 mol) and sodium bicarbonate(270 g, 3.22 mol) were charged in to a round bottomed flask withstirring under nitrogen atmosphere and cooled to 0-5° C. 2-Chloroacetylchloride (218 g, 1.93 mol) was added drop wise at 0-5° C. over a periodof 1 hour. The reaction was stirred at 0-5° C. for 1 hour. Aftercompletion of the reaction, purified water (2.86 L) was added andstirred at 25-30° C. for 15 minutes. The layers were then separated. Theorganic layer was washed with water (2×2.86 L) and with brine (1.43 L).The aqueous layers were combined and extracted with ethyl acetate (1.43L). The organic layers were dried with sodium sulphate, filtered, andconcentrated at 50-55° C. under vacuum (500-600 mm Hg) to ⅖^(ths)volume. Hexanes (2.86 L) were added and the mixture was stirred at25-30° C. for 1 hour. The solid was filtered, washed with hexanes (1.43L), and dried at 45-50° C. under vacuum (500-600 mm Hg) to give2-chloro-N-(2-isopropyl-5-methylphenyl)acetamide as an off-white solid(270 g, 66%): mp 97-99° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H), 7.60(s, 1H), 7.20 (d, J=7.95 Hz, 1H), 7.04 (d, J=7.89 Hz, 1H), 4.25 (s, 2H),2.99 (q, J=6.78 Hz, 1H), 2.34 (s, 3H), 1.26 (d, J=6.84 Hz, 6H); ¹³C NMR(100 MHz, CDCl₃) δ 164.07, 137.28, 136.33, 132.95, 127.35, 125.62,124.46, 43.21, 27.86, 22.98, 21.00; ESIMS m/z 226 ([M+H]⁺).

Step 2.

2-Chloro-N-(2-isopropyl-5-methylphenyl)acetamide (290 g, 1.28 mol) andacetone (1.60 L) were charged in to a round bottomed flask with stirringunder a nitrogen atmosphere. Potassium thiocyanate (250 g, 2.57 mol) wasadded in portions over a period of 30 minutes maintaining thetemperature at 15-20° C. The reaction was stirred at 15-20° C. for 10minutes after which time the temperature was slowly raised 53-55° C. andmaintained at 53-55° C. for 3 hours. The reaction was then cooled to20-25° C., cesium carbonate (20.9 g, 0.0641 mol) was added, and thereaction mixture was stirred at 20-25° C. for 30 minutes. Aftercompletion, the reaction mixture was filtered through Celite®, washedwith acetone (1.45 L), and the filtrate collected. The filtrate wasconcentrated at 40-45° C. under vacuum (500-600 mm Hg) providing asyrup. The syrup was dissolved in ethyl acetate (2.90 L), washed withwater (2×2.90 L) and with brine (1.45 L). The organic layers were driedwith sodium sulphate, filtered, and concentrated at 50-55° C. undervacuum (500-600 mm Hg) to provide the title compound as a dark brownsyrup (345 g, 99%).

Example 84: Preparation of(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50)

A round-bottomed flask was charged with2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (CA49) (1.30 g,5.23 mmol), 4-Nitrophenyl chloroformate (1.06 g, 5.23 mmol) and cesiumcarbonate (1.71 g, 5.23 mmol) were dissolved in acetonitrile (13 mL).The reaction mixture was stirred at room temperature for 1.5 hours. Thereaction was diluted with dichloromethane and adsorbed onto silica gel.Purification by flash column chromatography using 0-100% ethylacetate/hexanes as eluent provided the title compound as a dark redsolid (1.88 g, 86%): ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.18 (m, 2H),7.39-7.27 (m, 4H), 6.92-6.83 (m, 1H), 4.14-4.00 (m, 2H), 2.61 (p, J=6.9Hz, 1H), 2.36 (d, J=0.7 Hz, 3H), 1.30-1.10 (m, 6H); ESIMS m/z 414([M+H]⁺).

Example 85: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5)

Method A.

To2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CA51) (0.030 g, 0.086 mmol) and cesium carbonate (0.028 g, 0.086 mmol)in anhydrous acetonitrile under nitrogen was added(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50) (0.039 g, 0.095 mmol) dropwise. The reaction mixture was stirredroom temperature for 3 hours. The crude mixture was concentrated invacuo. Purification by flash column chromatography using 10-60% ethylacetate/hexanes as eluent provided the title compound as an orange foam(0.036 g, 67%).

Method B.

To a solution of3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) (3.00 g, 8.01 mmol) in toluene (20.0 mL) was added cesiumcarbonate (0.261 g, 0.801 mmol). To this was added2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (CA49) (1.99 g,8.01 mmol) in acetonitrile (20.0 mL). The reaction was stirred at roomtemperature for 3.5 hours after which time the reaction mixture wasconcentrated. Acetone (200 mL) was added and the solid was filtered. Thefiltrate was concentrated providing a red solid. The red solid wasdissolved in acetone, hexanes was added until precipitate was formed.The solid was filtered and the filtrate was concentrated. Purificationby flash column chromatography using 0-20% acetone/dichloromethane aseluent provide the title compound as an off-white solid (3.10 g, 62%).

Method C.

3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) (432 g, 1.15 mol) and acetonitrile (1.51 L) were charged in to around bottomed flask with stirring under nitrogen atmosphere. A solutionof 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (CA49) (320g, 1.29 mol) in acetonitrile (1.43 L) was added at 25-30° C. Thereaction was stirred at 25-30° C. for 20 hours. After completion of thereaction, the reaction mixture was filtered, washed with acetonitrile(2.16 L), heptane (464 mL), and dried at 50-55° C. under vacuum (500-600mm Hg) to give the title compound as an off-white solid (540 g, 75%).

Example 86: Preparation of2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(CB35)

3-Bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (0.30 g,1.0 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(CB4) (0.25 g, 1.0 mmol), sodium bicarbonate (0.25 g, 2.9 mmol),tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol), dioxane(3.9 mL), and water (0.97 mL). in a 0.5-2.0 mL vial was capped andheated at 140° C. for 30 minutes in a Biotage Initiator® microwavereactor with external IR-sensor temperature monitoring from the side ofthe vessel. The reaction mixture was diluted with ethyl acetate andwashed with water. The aqueous layer was extracted with ethyl acetate.The organic layers were poured through a phase separator andconcentrated. Purification by flash column chromatography using 0-20%ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent providedthe title compound as a white solid (0.19 g, 57%): ¹H NMR (400 MHz,CDCl₃) δ 10.33 (s, 1H), 8.61 (s, 1H), 8.19 (dd, J=8.0, 1.6 Hz, 1H), 8.13(t, J=1.1 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.86-7.78 (m, 2H), 7.45-7.37(m, 2H), 2.77 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.01; ESIMS m/z 348([M+H]⁺)

The following compounds were prepared in accordance to the procedure inExample 86.

Preparation of2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde(CB36)

The title compound was prepared as described in Example 86 using3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) and2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(CB5) and isolated as a white solid (0.569 g, 47%): ¹H NMR (400 MHz,CDCl₃) δ 10.42 (d, J=0.7 Hz, 1H), 8.61 (s, 1H), 8.12 (ddd, J=8.1, 1.5,0.8 Hz, 1H), 8.05-7.95 (m, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0Hz, 1H), 7.45-7.39 (m, 2H); ESIMS m/z 352 ([M+H]⁺).

Example 87: Preparation of N-(2-ethylphenyl)-1,2,3,4-thiatriazol-5-amine(CB37)

To a stirred and cooled mixture ofN-(2-ethylphenyl)hydrazinecarbothioamide (0.500 g, 2.56 mmol) and aceticacid (2.00 mL, 17.5 mmol) was added sodium nitrite (0.177 g, 2.56 mmol)in water (1 mL). The mixture turned yellow upon addition and thereaction was stirred for 1 hour. The solid was filtered and the titlecompound was obtained as an orange solid (0.389 g, 73%): ¹H NMR (400MHz, CDCl₃) δ 9.02 (s, 1H), 7.42-7.28 (m, 4H), 2.76 (q, J=7.5 Hz, 2H),1.25 (t, J=7.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 138.69, 137.90,130.38, 128.28, 128.14, 121.60, 24.73, 14.79; ESIMS m/z 179 ([M+H]—N₂+).

The following compounds were prepared in accordance to the procedure inExample 87.

Preparation ofN-(2-isopropyl-4-methoxyphenyl)-1,2,3,4-thiatriazol-5-amine (CB38)

The title compound was prepared as described in Example 87 usingN-(2-isopropyl-4-methoxyphenyl)hydrazinecarbothioamide (CB53) andisolated as an orange solid (0.531 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ8.51 (s, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.91 (d, J=2.9 Hz, 1H), 6.80 (dd,J=8.7, 2.9 Hz, 1H), 3.85 (s, 3H), 3.17 (dq, J=13.7, 6.9 Hz, 1H), 1.22(d, J=6.9 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 160.18, 146.49, 131.57,128.24, 126.34, 113.46, 112.61, 55.95, 28.88, 23.81.

Preparation ofN-(5-fluoro-2-isopropylphenyl)-1,2,3,4-thiatriazol-5-amine (CB39)

The title compound was prepared as described in Example 87 usingN-(5-fluoro-2-isopropylphenyl)hydrazinecarbothioamide and isolated as ared solid (0.520 g, 64%): ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J=8.7, 6.2Hz, 1H), 7.13 (dd, J=9.3, 2.6 Hz, 1H), 7.04 (ddd, J=8.7, 7.9, 2.7 Hz,1H), 3.19 (dt, J=13.7, 6.9 Hz, 2H), 1.24 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376MHz, CDCl₃) δ −113.32; ESIMS m/z 237 ([M−H]⁻).

Preparation ofN-(4-fluoro-2-isopropylphenyl)-1,2,3,4-thiatriazol-5-amine (CB40)

The title compound was prepared as described in Example 87 usingN-(4-fluoro-2-isopropylphenyl)hydrazinecarbothioamide and isolated as ared solid (0.520 g, 64%): ¹H NMR (400 MHz, CDCl₃) δ (400 MHz, CDCl₃) δ8.63 (s, 1H), 7.35 (dd, J=8.7, 5.2 Hz, 1H), 7.11 (dd, J=9.8, 3.0 Hz,1H), 7.00 (ddd, J=8.7, 7.5, 2.9 Hz, 1H), 3.20 (pd, J=6.8, 1.7 Hz, 1H),1.23 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ −111.20; ESIMS m/z238 ([M]⁺).

Preparation of N-(2-isopropylphenyl)-1,2,3,4-thiatriazol-5-amine (CB41)

The title compound was prepared as described in Example 87 usingN-(2-isopropylphenyl)hydrazinecarbothioamide and isolated as a mustardyellow solid (0.574 g, 71%): ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H),7.44-7.39 (m, 1H), 7.39-7.34 (m, 2H), 7.34-7.29 (m, 1H), 3.21 (p, J=6.7Hz, 1H), 1.26 (d, J=6.9 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 179.95,143.24, 138.10, 128.78, 128.17, 127.56, 122.85, 28.54, 23.73.

Example 88: Preparation of(Z)-1-ethyl-3-(2-ethyl-4-(2-ethylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB42)

N-(2-Ethylphenyl)-1,2,3,4-thiatriazol-5-amine (CB37) (0.350 g, 1.70mmol) was dissolved in tetrahydrofuran (5 mL). Ethyl isocyanate (0.121mL, 1.53 mmol) and triethylamine (5 drops) were added. The reaction wasstirred at room temperature overnight. The solution was concentrated togive the title compound as an orange oil (0.484 g, 89%): ¹H NMR (400MHz, CDCl₃) δ 7.48-7.36 (m, 2H), 7.36-7.29 (m, 1H), 7.19 (dd, J=7.8, 1.4Hz, 1H), 5.54-5.43 (m, 1H), 3.68 (q, J=7.2 Hz, 2H), 3.26 (qdd, J=7.3,5.9, 4.8 Hz, 2H), 2.51 (qd, J=7.6, 2.9 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H),1.18 (t, J=7.6 Hz, 3H), 1.12 (t, J=7.3 Hz, 3H); ESIMS m/z 320 ([M]⁺).

The following compounds were prepared in accordance to the procedure inExample 88.

Preparation of(Z)-1-ethyl-3-(2-ethyl-4-(2-isopropyl-4-methoxyphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB43)

The title compound was prepared as described in Example 88 usingN-(2-isopropyl-4-methoxyphenyl)-1,2,3,4-thiatriazol-5-amine (CB38) andisolated as a dark brown oil (0.693 g, 82%): ¹H NMR (400 MHz, CDCl₃) δ7.10 (d, J=8.7 Hz, 1H), 6.94 (d, J=2.8 Hz, 1H), 6.83 (dd, J=8.7, 2.8 Hz,1H), 5.48 (t, J=5.8 Hz, 1H), 3.84 (s, 3H), 3.67 (q, J=7.3 Hz, 2H), 3.08(q, J=7.3 Hz, 2H), 2.70 (p, J=6.9 Hz, 1H), 1.34 (dt, J=10.0, 7.3 Hz,3H), 1.18 (t, J=6.9 Hz, 6H), 1.12 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 167.43, 165.14, 161.07, 148.57, 144.62, 129.93, 126.14, 113.06,112.28, 55.82, 46.36, 39.68, 36.02, 29.31, 24.01, 15.31, 14.56; ESIMSm/z 364 ([M]⁺).

Preparation of(Z)-1-ethyl-3-(2-ethyl-4-(5-fluoro-2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB44)

The title compound was prepared as described in Example 88 usingN-(5-fluoro-2-isopropylphenyl)-1,2,3,4-thiatriazol-5-amine (CB39) andisolated as a dark brown oil (0.316 g, 37%): ¹H NMR (400 MHz, CDCl₃) δ7.41 (dd, J=8.8, 6.0 Hz, 1H), 7.21-7.13 (m, 1H), 6.92 (dd, J=8.7, 2.7Hz, 1H), 5.46 (d, J=6.8 Hz, 1H), 3.75-3.56 (m, 2H), 3.36-3.15 (m, 2H),2.72 (p, J=6.8 Hz, 1H), 1.34 (t, J=7.2 Hz, 3H), 1.18 (dd, J=10.9, 6.9Hz, 6H), 1.13 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −115.44;ESIMS m/z 352 ([M]⁺).

Preparation of(Z)-1-ethyl-3-(2-ethyl-4-(4-fluoro-2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB45)

The title compound was prepared as described in Example 88 usingN-(4-fluoro-2-isopropylphenyl)-1,2,3,4-thiatriazol-5-amine (CB40) andisolated as a red oil (0.340 g, 44%): ¹H NMR (400 MHz, CDCl₃) δ7.18-7.08 (m, 2H), 7.00 (ddd, J=8.7, 7.6, 2.9 Hz, 1H), 5.46 (t, J=5.8Hz, 1H), 3.67 (q, J=7.2 Hz, 2H), 3.36-3.17 (m, 2H), 2.72 (td, J=6.8, 1.8Hz, 1H), 1.33 (t, J=7.3 Hz, 3H), 1.22-1.07 (m, 9H); ¹⁹F NMR (376 MHz,CDCl₃) δ −111.31; ESIMS m/z 352 ([M]⁺).

Preparation of(Z)-1-ethyl-3-(2-ethyl-4-(2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB46)

The title compound was prepared as described in Example 88 usingN-(2-isopropylphenyl)-1,2,3,4-thiatriazol-5-amine (CB41) and isolated asa red oil (0.788 g, 87%): ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.44 (m, 2H),7.34-7.28 (m, 1H), 7.19-7.15 (m, 1H), 3.68 (q, J=7.2 Hz, 2H), 3.34-3.19(m, 3H), 2.75 (p, J=6.9 Hz, 1H), 1.34 (t, J=7.2 Hz, 3H), 1.20 (dd,J=7.8, 6.8 Hz, 6H), 1.12 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ167.07, 165.09, 152.63, 147.13, 133.37, 130.65, 128.95, 127.37, 127.30,46.36, 39.67, 36.01, 29.08, 24.07, 15.32, 14.56; ESIMS m/z 334 ([M]⁺).

Example 89: Preparation of2-ethyl-4-(2-ethylphenyl)-5-imino-1,2,4-thiadiazolidin-3-one (CB47)

(Z)-1-Ethyl-3-(2-ethyl-4-(2-ethylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB42) (0.484 g, 1.51 mmol) was dissolved in methanol (150 mL). Sodiumhydroxide (3.36 g, 84.0 mmol) was slowly added and the reaction wasstirred at room temperature. After 4 hours the solution was concentratedto ½ volume, poured onto water, and extracted with ethyl acetate. Theorganics were dried and concentrated to give the title compound as anorange solid (0.249 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.32 (m,2H), 7.30 (dd, J=5.4, 1.5 Hz, 1H), 7.25-7.20 (m, 1H), 3.65 (q, J=7.2 Hz,2H), 3.39-3.19 (m, 1H), 2.73 (q, J=7.6 Hz, 2H), 1.26-1.13 (m, 6H); ¹³CNMR (101 MHz, CDCl₃) δ 173.32, 165.49, 141.20, 135.74, 130.42, 129.31,127.67, 126.01, 39.50, 24.79, 15.22, 14.93; ESIMS m/z 250 ([M]⁺).

The following compounds were prepared in accordance to the procedure inExample 89.

Preparation of2-ethyl-5-imino-4-(2-isopropyl-4-methoxyphenyl)-1,2,4-thiadiazolidin-3-one(CB48)

The title compound was prepared as described in Example 89 using(Z)-1-ethyl-3-(2-ethyl-4-(2-isopropyl-4-methoxyphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB43) and isolated as a red oil (0.442 g, 63%): ¹H NMR (400 MHz, CDCl₃)δ 7.22 (d, J=8.6 Hz, 1H), 6.90 (d, J=2.9 Hz, 1H), 6.74 (dd, J=8.7, 2.9Hz, 1H), 3.83 (s, 3H), 3.68-3.57 (m, 2H), 3.24-3.13 (m, 2H), 1.20 (dd,J=8.5, 7.1 Hz, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 165.84, 160.88, 148.76,129.20, 126.94, 126.13, 113.50, 112.05, 55.90, 39.44, 28.90, 23.87,15.23; ESIMS m/z 293 ([M]⁺).

Preparation of2-ethyl-4-(5-fluoro-2-isopropylphenyl)-5-imino-1,2,4-thiadiazolidin-3-one(CB49)

The title compound was prepared as described in Example 89 using(Z)-1-ethyl-3-(2-ethyl-4-(5-fluoro-2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB44) and isolated as a red solid (0.145 g, 56%): ¹H NMR (400 MHz,CDCl₃) δ 7.38-7.28 (m, 1H), 7.06-6.94 (m, 2H), 3.64 (q, J=7.1 Hz, H),3.18 (p, J=6.8 Hz, 1H), 1.30-1.05 (m, 10H); ¹⁹F NMR (376 MHz, CDCl₃) δ−115.44; ESIMS m/z 281 ([M]⁺).

Preparation of2-ethyl-4-(4-fluoro-2-isopropylphenyl)-5-imino-1,2,4-thiadiazolidin-3-one(CB50)

The title compound was prepared as described in Example 89 using(Z)-1-ethyl-3-(2-ethyl-4-(4-fluoro-2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB45) and isolated as a yellow oil (0.110 g, 38%): ¹H NMR (400 MHz,CDCl₃) δ 7.32-7.25 (m, 1H), 7.08 (dd, J=9.9, 2.9 Hz, 1H), 6.92 (ddd,J=8.7, 7.6, 2.9 Hz, 1H), 3.75-3.57 (m, 3H), 3.32-3.13 (m, 1H), 1.23 (d,J=6.9 Hz, 6H), 1.19 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ−110.83; ESIMS m/z 281 ([M]⁺).

Preparation of2-ethyl-5-imino-4-(2-isopropylphenyl)-1,2,4-thiadiazolidin-3-one (CB51)

The title compound was prepared as described in Example 89 using(Z)-1-ethyl-3-(2-ethyl-4-(2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea(CB46) and isolated as a red oil (0.421 g, 65%): ¹H NMR (400 MHz, CDCl₃)δ 7.42-7.34 (m, 2H), 7.31-7.27 (m, 1H), 7.22 (dd, J=9.2, 6.5 Hz, 1H),4.06 (s, 1H), 3.65 (d, J=8.5 Hz, 2H), 3.34-3.13 (m, 1H), 1.21 (m, 9H);ESIMS m/z 263 ([M]⁺).

Example 90: Preparation of(Z)-1-(2-ethyl-4-(2-ethylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB10)

A solution of3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) (0.100 g, 0.249 mmol) in acetonitrile (4 mL) was heated at70° C. for 2 hours. The reaction was cooled to room temperature, andthen 2-ethyl-4-(2-ethylphenyl)-5-imino-1,2,4-thiadiazolidin-3-one (CB47)(0.0660 g, 0.265 mmol) in tetrahydrofuran and triethylamine (3 drops)were added. The reaction was stirred overnight. The solution was dilutedin ethyl acetate and washed with water. The organics were extracted,dried, and concentrated. Purification by reverse-phase preparative HPLCusing 0-90% acetonitrile/water (0.1% acetic acid) as eluent provided thetitle compound as a white solid (0.045 g, 26%).

The following compounds were prepared in accordance to the procedure inExample 90.

Preparation of(Z)-1-(2-ethyl-4-(2-isopropyl-4-methoxyphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB11)

The title compound was prepared as described in Example 90 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) and2-ethyl-5-imino-4-(2-isopropyl-4-methoxyphenyl)-1,2,4-thiadiazolidin-3-one(CB48) and isolated as a yellow solid (0.016 g, 7%).

Preparation of(Z)-1-(2-ethyl-4-(5-fluoro-2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB12)

The title compound was prepared as described in Example 90 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) and2-ethyl-4-(5-fluoro-2-isopropylphenyl)-5-imino-1,2,4-thiadiazolidin-3-one(CB49) and isolated as a yellow oil (0.068 g, 40%).

Preparation of(Z)-1-(2-ethyl-4-(4-fluoro-2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB13)

The title compound was prepared as described in Example 90 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) and2-ethyl-4-(4-fluoro-2-isopropylphenyl)-5-imino-1,2,4-thiadiazolidin-3-one(CB50) and isolated as a yellow oil (0.018 g, 14%).

Preparation of(Z)-1-(2-ethyl-4-(2-isopropylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB14)

The title compound was prepared as described in Example 90 using3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoylazide (C34) and2-ethyl-5-imino-4-(2-isopropylphenyl)-1,2,4-thiadiazolidin-3-one (CB51)and isolated as a yellow solid (0.047 g, 23%).

Example 91: Preparation ofN-(2-ethyl-4-methoxyphenyl)hydrazinecarbothioamide (CB52)

Step 1.

To solution of 2-ethyl-4-methoxyaniline (4.5 g, 30 mmol) andtriethylamine (6.0 g, 60 mmol) in dichloromethane (31 mL) was addedthiophosgene (3.4 g, 30 mmol) was added drop wise at 0° C. over theperiod of 1 hour. After completion, the reaction mixture was poured intoice-water (100 mL) and extracted with ethyl acetate (3×200 mL) andwashed with ice water (2×100 mL), followed by brine (2×50 mL). Theorganic phase was dried over sodium sulfate, filtered, and evaporatedunder reduced pressure. Purification by flash column chromatographyusing 0-10% ethyl acetate/hexanes as eluent provided2-ethyl-1-isothiocyanato-4-methoxybenzene as yellow oil (4.9 g, 25mmol), which was taken onto the next step immediately.

Step 2.

To a solution of 2-ethyl-1-isothiocyanato-4-methoxybenzene (4.9 g, 25mmol) in ethanol (22 mL), was added slowly, hydrazine-hydrate (1.3 g, 28mmol). The reaction mixture was stirred at room temperature for 18hours. The reaction mixture was evaporated under reduced pressure anddiluted with ethyl acetate (250 mL) and washed with water (2×50 mL),followed by brine (2×50 mL). The organic phase was dried over sodiumsulfate, filtered, and evaporated under reduced pressure. Purificationby flash column chromatography using 0-40% ethyl acetate/hexanes aseluent provided the title compound as a white solid (4.9 g, 86%): mp113-115° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.89 (s, 1H),7.20-7.19 (m, 1H), 6.77-6.71 (m, 2H), 4.71 (bs, 2H), 3.74 (s, 3H),2.52-2.47 (m, 2H), 1.13-1.08 (m, 3H); ESIMS m/z 224 ([M−H]⁻).

The following compounds were prepared in accordance to the procedure inExample 91.

Preparation of N-(2-isopropyl-4-methoxyphenyl)hydrazinecarbothioamide(CB53)

The title compound was prepared as described in Example 88 using2-isopropyl-4-methoxyaniline and isolated as a white solid (9.5 g): mp153-156° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.96 (s, 1H),7.12-7.10 (m, 1H), 6.78-6.78 (m, 2H), 4.71 (bs, 2H), 3.17 (s, 3H),3.05-3.00 (m, 1H), 1.14 (d, J=6.6 Hz, 6H); ESIMS m/z 238 ([M−H]⁻).

Example 92: Preparation of3-(4-(7-oxabicyclo[4.1.0]heptan-1-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB54)

To a solution of3-(2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB10) (3.11 g, 8.07 mmol) in diethyl ether (60 mL) was addedmeta-chloroperoxybenzoic acid (70%; 2.79 g, 11.3 mmol) slowly at 0° C.The reaction was stirred and allowed to gradually warm to roomtemperature, then stirring was continued for 18 hours. The solution wasdiluted in diethyl ether, washed with sodium bicarbonate, extracted withdiethyl ether, washed with water, and extracted again with diethylether. The organics were dried, filtered, and concentrated providing thetitle compound as a white solid (2.5 g, 77%) which was used withoutfurther purification: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.20-8.11(m, 2H), 7.84-7.77 (m, 2H), 7.52-7.46 (m, 2H), 7.39 (dt, J=8.0, 1.0 Hz,2H), 3.12 (dd, J=3.1, 1.7 Hz, 1H), 2.34 (ddd, J=14.9, 8.5, 5.3 Hz, 1H),2.09-1.95 (m, 2H), 1.74-1.45 (m, 4H), 1.42-1.28 (m, 1H); ¹⁹F NMR (376MHz, CDCl₃) δ −58.03; ESIMS m/z 402 ([M+H]⁺).

Example 93: Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanone(CB55)

To a stirred solution of indium chloride (1.259 g, 5.69 mmol) in 15 mLof dry THF in a 100 mL flask was added a solution of3-(4-(7-oxabicyclo[4.1.0]heptan-1-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(CB54) (1.14 g, 2.85 mmol) in dry tetrahydrofuran (10 mL). Stirring wascontinued under nitrogen for 24 hours, then the solution was dilutedwith diethyl ether (50 mL) and washed with water, dried, andconcentrated in vacuo. Purification by flash column chromatography using0-60% ethyl acetate/hexanes as eluent provided the title compound as awhite solid (0.566 g, 35%): ¹H NMR (400 MHz, CDCl₃) δ ¹H NMR (400 MHz,CDCl₃) δ 8.54 (s, 1H), 8.16 (dd, J=8.6, 2.1 Hz, 2H), 7.83-7.72 (m, 2H),7.43-7.33 (m, 2H), 7.30-7.21 (m, 2H), 3.68 (dd, J=12.2, 5.4 Hz, 1H),2.61-2.41 (m, 2H), 2.37-2.24 (m, 1H), 2.23-1.92 (m, 3H), 1.85-1.60 (m,2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 402 ([M+H]⁺).

Example 94: Preparation of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanamine(CB56)

To a dry flask was added a solution of2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanone(CB55) (0.98 g, 2.4 mmol) in dry methanol (30 mL). The flask wasevacuated/backfilled with nitrogen and ammonium acetate (2.6 g, 34 mmol)was added, followed by sodium cyanoborohydride (0.18 g, 2.9 mmol). Thereaction was stirred at room temperature overnight. The solution wasquenched with water and extracted with ethyl acetate. The organics weredried, filtered, and concentrated to provide the title compound as awhite solid (0.42 g, 34%): ¹H NMR indicated the presence of 2 isomers,which were not separated. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (two s, 1H),8.14-8.03 (m, 4H), 7.66-7.60 (m, 2H), 7.53-7.40 (m, 2H), 3.47-3.16 (brs, 2H), 3.29 (td, J=11.0, 3.8 Hz, 1H), 2.59 (td, J=11.6, 11.1, 3.7 Hz,1H), 2.17-2.04 (m, 1H), 1.86-1.68 (m, 3H), 1.68-1.30 (m, 4H); ESIMS m/z402 ([M]⁺).

Example 95: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexyl)urea(FB15)

To2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanamine(CB56) (0.200 g, 0.497 mmol) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50) (0.205 g, 0.497 mmol) were dissolved in acetonitrile (10 mL) in avial. Cesium carbonate (0.162 g, 0.497 mmol) was added, and the reactionwas stirred at room temperature for 25 hours. The solution was adsorbedonto silica. Purification by reverse-phase flash column chromatographyusing 0-100% acetonitrile/water as eluent afforded the title compound asa red oil (0.020 g, 6%).

The following compounds were prepared in accordance to the procedure inExample 95.

Preparation of(Z)-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-1-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB51)

The title compound was prepared as described in Example 95 usingN-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CB24) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50), purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolatedas a pale orange foam (0.160 g, 63%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(FB52)

The title compound was prepared as described in Example 95 using2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB28) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50), purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolatedas a brown oil (0.018 g, 9%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)urea(FB53)

The title compound was prepared as described in Example 95 using2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine(CB29) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50), purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolatedas a brown glassy foam (0.084 g, 46%).

Preparation of(Z)-1-ethyl-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB54)

The title compound was prepared as described in Example 95 usingN-ethyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CB25) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50), purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolatedas a red solid (0.075 g, 56%).

Preparation of(Z)-1-allyl-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB61)

The title compound was prepared as described in Example 95 usingN-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)prop-2-en-1-amine(CB26) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50), purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolatedas a brown oil (0.040 g, 43%).

Preparation of(Z)-1-(cyclopropylmethyl)-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB62)

The title compound was prepared as described in Example 95 usingN-(cyclopropylmethyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine(CB27) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50), purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolatedas red-orange oil (0.127 g, 60%).

Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropyl)urea(FB63)

The title compound was prepared as described in Example 95 using1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanamine(CB30) and(Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate(CA50), purified by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolatedas red oil (0.104 g, 37%).

Example 96: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxo-1,3-thiazinan-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB41)

3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C34a) (0.18 g, 0.47 mmol), 1-(2-isopropyl-5-methylphenyl)thiourea (0.10g, 0.50 mmol), and cesium carbonate (0.21 g, 0.63 mmol) in acetonitrile(2.3 mL) were stirred at room temperature overnight. The reaction wasdiluted with ethyl acetate and washed with water. The organic layerswere dried over sodium sulfate, filtered, and concentrated. The crudematerial was dissolved in butanone (2.3 mL) followed by addition ofacryloyl chloride (0.045 mL, 0.55 mmol). The reaction was heated at 40°C. for 4 hours. The reaction was cooled and concentrated. Purificationby flash column chromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent followed by drying in a vacuum ovenprovided the title compound as a yellow oil (0.13 g, 44%).

Example 97: Preparation of1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-one(CB57)

3-(4-Bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C52)(11 g, 29 mmol), copper(I) iodide (0.55 g, 2.9 mmol), potassiumphosphate (18 g, 86 mmol), and pentane-2,4-dione (8.9 mL, 86 mmol) weredissolved in dimethylsulfoxide (120 mL) in a 500 mL round bottomedflask. The reaction was heated at 110° C. for 19 hours. The solution wascooled to room temperature and then quenched with hydrogen chloride (2N). The excess base was removed by gravity filtration and the filtratewas extracted with ethyl acetate. The organics were washed with water,extracted, dried, and concentrated. Purification by flash columnchromatography using 0-30% ethyl acetate/hexanes afforded the titlecompound as a pure orange solid (3.7 g, 35%): ¹H NMR (400 MHz, CDCl₃) δ8.56 (s, 1H), 8.17 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.39 (dt,J=8.1, 1.0 Hz, 2H), 7.33 (dd, J=8.1, 0.6 Hz, 2H), 3.76 (s, 2H), 2.19 (s,3H); ESIMS m/z 361 ([M]⁺).

Example 98: Preparation of1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB58)

1-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-one(CB57) (1.0 g, 2.8 mmol) and ammonium acetate (1.7 g, 22 mmol) werecombined in dry methanol (22 mL)_and stirred at room temperature whilesodium cyanoborohydride (0.17 g, 2.7 mmol) was added in 3 equal portionsover 30 minutes. The reaction was stirred overnight. The reaction wasconcentrated and partitioned between aqueous potassium carbonate anddiethyl ether. The layers were separated, dried, filtered, andconcentrated. Purification by reverse-phase flash column (C18)chromatography using 0-100% acetonitrile/water as eluent provided thetitle compound as a tan solid (1.0 g, 38%): mp 140-160° C.; ¹H NMR (400MHz, CDOD₃) d 9.13 (s, 1H), 8.09 (d, J=8.0 Hz, 2H), 8.00 (d, J=9.0 Hz,2H), 7.52-7.43 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 3.40-3.33 (m, 1H), 2.86(t, J=6.7 Hz, 1H), 2.77 (dd, J=13.3, 7.3 Hz, 1H), 1.18 (d, J=6.2 Hz, 3H)(NH ₂ not observed); ESIMS m/z 363 ([M+H]⁺).

Example 99: Preparation of(R)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(2S,3S)-2,3-dihydroxysuccinate(CB59)

To1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB58) (0.60 g, 1.7 mmol) in methanol (10 mL) was added(2S,3S)-2,3-dihydroxysuccinic acid (0.25 g, 1.7 mmol). The resultantsolid was filtered and air dried overnight: mp 182-185° C. The solid wasredissolved in methanol (10 mL) and heated to reflux (˜65° C.). Thesolution was cooled to room temperature and let stand overnight. Thewhite solid that formed was filtered and air-dried to give the titlecompound as a white solid (0.40 g, 46%): mp 191-194° C.; ¹H NMR (400MHz, CDOD₃) d 9.16 (s, 1H), 8.15 (d, J=8.2 Hz, 2H), 8.02 (d, J=9.1 Hz,2H), 7.50 (dd, J=9.2, 1.0 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.40 (s, 2H),3.59 (dt, J=8.1, 6.2 Hz, 1H), 3.07 (dd, J=13.6, 6.1 Hz, 1H), 2.88 (dd,J=13.6, 8.3 Hz, 1H), 1.29 (d, J=6.5 Hz, 3H) (OH and NH ₂ not observed).

The following compounds were prepared in accordance to the procedure inExample 99.

Preparation of(S)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(2R,3R)-2,3-dihydroxysuccinate(CB60)

The title compound was prepared as described in Example 99 using1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB58) and (2R,3R)-2,3-dihydroxysuccinic acid and isolated as a whitesolid (0.70 g, 49%): mp 187-191° C.; ¹H NMR ¹H NMR (400 MHz, DMSO-d₆) d9.40 (s, 1H), 8.08 (dd, J=8.6, 3.6 Hz, 4H), 7.63 (dt, J=8.1, 1.0 Hz,2H), 7.49-7.32 (m, 2H), 3.81 (s, 2H), 3.47 (dt, J=8.5, 6.2 Hz, 1H), 3.01(dd, J=13.4, 5.5 Hz, 1H), 2.74 (dd, J=13.4, 8.7 Hz, 1H), 1.13 (d, J=6.4Hz, 3H) (OH and NH ₂ not observed).

Example 100: Preparation of(R)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB61)

(R)-1-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(2S,3S)-2,3-dihydroxysuccinate(CB59) (0.35 g, 0.68 mmol) was slurried in methanol (20 mL) and SCXsilica gel (2 g). The solution was stirred for 3 hours, filtered, andwashed with methanol (20 mL). The compound was eluted from the SCXsilica gel using ammonium hydroxide (5% in MeOH, 25 mL). The filtratewas concentrated providing the title compound as a white solid (0.22 g,87%): mp 84-88° C.; ¹H NMR (400 MHz, CDCl₃) d 8.56 (s, 1H), 8.13 (d,J=8.2 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.44-7.35 (m, 2H), 7.31 (d, J=8.1Hz, 2H), 3.29-3.15 (m, 1H), 2.78 (dd, J=13.2, 5.4 Hz, 1H), 2.60 (dd,J=13.2, 8.0 Hz, 1H), 1.49 (s, 2H), 1.15 (d, J=6.3 Hz, 3H).

The following compounds were prepared in accordance to the procedure inExample 100.

Preparation of(S)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB62)

The title compound was prepared as described in Example 100 using(S)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(2R,3R)-2,3-dihydroxysuccinate(CB60) and isolated as a white solid (0.40 g, 94%): mp 84-86° C.; ¹H NMR(400 MHz, CDCl₃) d 8.56 (s, 1H), 8.13 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.0Hz, 2H), 7.44-7.35 (m, 2H), 7.35-7.28 (m, 2H), 3.29-3.16 (m, 1H), 2.78(dd, J=13.2, 5.3 Hz, 1H), 2.60 (dd, J=13.2, 8.0 Hz, 1H), 1.15 (d, J=6.3Hz, 3H) (NH ₂ not observed).

Example 101: Preparation of(R,Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(FB45)

To(R)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB61) (0.12 g, 0.32 mmol) and sodium bicarbonate (0.10 g, 1.2 mmol) indichloromethane/water (2:1, 3.1 mL) in an ice bath was added triphosgene(0.052 g, 0.18 mmol). The reaction was quenched with few drops of waterand diluted with dichloromethane. The reaction mixture was filteredthrough phase separator and concentrated. The residue was dissolved inacetonitrile (2 mL) and 1-(2-isopropyl-5-methylphenyl)thiourea (0.069 g,0.33 mmol) and cesium carbonate (0.14 g, 0.42 mmol) were added in singleportions. The reaction was stirred overnight at room temperature.Additional portions of 1-(2-isopropyl-5-methylphenyl)thiourea (0.070 g,0.33 mmol) and cesium carbonate (0.070 g, 0.21 mmol) were added and thereaction was stirred overnight. Ethanol (4 mL), methyl 2-bromoacetate(0.10 mL, 0.96 mmol), and sodium acetate (0.079 g, 0.96 mmol) were addedand the reaction was heated at 60° C. for 6 hours. The reaction wascooled and stirred at room temperature over the weekend. The reactionwas diluted with water and extracted with ethyl acetate (2×). Theorganic layers were dried with sodium sulfate, filtered, andconcentrated. Purification by flash column chromatography using 0-100%ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent providedthe title compound as a yellow oil (0.039 g, 19%).

The following compounds were prepared in accordance to the procedure inExample 101.

Preparation of(S,Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)urea(FB46)

The title compound was prepared as described in Example 101 using(S)-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine(CB62) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as anoff-white foam (0.045 g, 24%).

Example 102: Preparation of tert-butylmethyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB63)

To tert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50) (0.021 g, 0.047 mmol) in anhydrous dimethylformamide (0.023 mL) at0° C. was added sodium hydride (60% oil dispersion, 0.012 g, 0.30 mmol)and stirred in ice bath for 5 minutes. Iodomethane (0.013 g, 0.094 mmol)was added and the yellow solution immediately turned white. After 10minutes, the reaction was quenched with water and extracted withdichloromethane. The organic layer was concentrated providing the titlecompound as a yellow oil (0.022 g, 97%): ¹H NMR (400 MHz, CDCl₃) δ 8.56(s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.39 (dt,J=8.0, 1.0 Hz, 2H), 7.37-7.20 (m, 2H), 3.47 (s, 2H), 2.86 (s, 2H), 1.57(s, 3H), 1.44 (d, J=13.7 Hz, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03;ESIMS m/z 463 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 102.

Preparation of tert-butylethyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB64)

The title compound was prepared as described in Example 102 usingtert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50) and iodoethane and isolated as a yellow oil (0.175 g, 100%): ¹HNMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.16-8.06 (m, 2H), 7.89-7.73 (m,2H), 7.45-7.36 (m, 2H), 7.31 (s, 2H), 3.42 (s, 2H), 3.23 (t, J=35.4 Hz,2H), 2.96-2.84 (m, 2H), 1.47 (s, 9H), 1.08 (s, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.03; ESIMS m/z 477 ([M+H]⁺).

Preparation of tert-butylallyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB65)

The title compound was prepared as described in Example 102 usingtert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50) and allyl bromide and isolated as a yellow oil (0.144 g, 99%): ¹HNMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.15-8.08 (m, 2H), 7.85-7.76 (m,2H), 7.39 (dq, J=7.8, 1.0 Hz, 2H), 7.30 (s, 2H), 5.76 (s, 1H), 5.12 (s,2H), 3.76 (d, J=45.8 Hz, 2H), 3.42 (s, 2H), 2.89 (d, J=0.7 Hz, 2H), 1.47(s, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z 489 ([M+H]⁺).

Preparation oftert-butyl(cyclopropylmethyl)(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate(CB66)

The title compound was prepared as described in Example 102 usingtert-butyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate(C50) and cyclopropylmethyl bromide and isolated as a clear oil (0.155g, 96%): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.16-8.07 (m, 2H),7.84-7.77 (m, 2H), 7.39 (dq, J=8.0, 0.9 Hz, 2H), 7.31 (s, 2H), 3.50 (t,J=7.6 Hz, 2H), 3.17-2.86 (m, 4H), 1.48 (s, 9H), 0.87 (ddd, J=11.2, 9.0,6.7 Hz, 1H), 0.49 (d, J=8.0 Hz, 2H), 0.21 (s, 2H); ¹⁹F NMR (376 MHz,CDCl₃) δ −58.03; ESIMS m/z 503 ([M+H]⁺).

Example 103: Preparation ofbenzyl(2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)carbamate(CB67)

A mixture of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole(C1) (4.28 g, 13.9 mmol),benzyl(2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamate(CB7) (6.12 g, 15.0 mmol), tri-tert-butylphosphonium tetrafluoroborate(0.390 g, 1.40 mmol), palladium(II)acetate (0.150 g, 0.680 mmol), andcesium fluoride (4.34 g, 28.6 mmol) in dioxane/water (4:1, 90 mL) washeated at 70° C. overnight. The reaction was cooled and diluted withbrine and extracted with ethyl acetate (2×). The organic layer was driedover sodium sulfate, filtered, and concentrated. Purification by flashcolumn chromatography using 0-100% ethyl acetate/hexanes as eluentprovided the title compound as a clear oil (1.16 g, 15%): ¹H NMR (400MHz, CDCl₃) δ 8.57 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.81 (d, J=9.0 Hz,2H), 7.44-7.32 (m, 7H), 7.19 (d, J=8.2 Hz, 2H), 5.12 (s, 2H), 4.56 (s,1H), 3.05 (s, 2H), 1.33 (s, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.02;ESIMS m/z 511 ([M+H]⁺).

The following compounds were prepared in accordance to the procedure inExample 103.

Preparation ofbenzyl(2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)carbamate(CB68)

The title compound was prepared as described in Example 103 usingbenzyl(2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate(CB8) and isolated as a clear oil (0.045 g, 24%): ¹H NMR (400 MHz,CDCl₃) δ 8.57 (s, 1H), 8.18-8.10 (m, 2H), 7.84-7.75 (m, 2H), 7.49-7.42(m, 2H), 7.39 (dq, J=9.0, 0.9 Hz, 2H), 7.31 (q, J=6.8, 6.4 Hz, 5H), 5.06(s, 2H), 4.52 (s, 1H), 3.45 (d, J=6.3 Hz, 2H), 1.38 (s, 6H); ¹⁹F NMR(376 MHz, CDCl₃) δ −58.03; ESIMS m/z 511 ([M+H]⁺).

Preparation ofbenzyl(1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropyl)carbamate(CB69)

The title compound was prepared as described in Example 103 using benzyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopropyl)carbamate(CB9) and isolated as a tan solid (2.19 g, 68%): mp 156-158° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.10 (d, J=8.1 Hz, 2H), 7.84-7.73 (m,2H), 7.42-7.30 (m, 6H), 7.26-7.25 (m, 3H), 5.10 (s, 2H), 4.96 (s, 1H),2.94 (s, 2H), 0.85 (s, 4H); ¹⁹F NMR (376 MHz, CDCl₃) δ −58.03; ESIMS m/z509 ([M+H]⁺).

Example 104: Preparation of(Z)-1-(5-fluoro-3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB64)

To(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5) (0.050 g, 0.080 mmol) and 2-fluorenone (0.0080 g, 0.044 mmol) inanhydrous acetonitrile (0.80 mL) was added Selectfluor® (0.062 g, 0.18mmol). The reaction was stirred at room temperature overnight.Purification by flash column chromatography using 0-100% ethylacetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided thetitle compound as a yellow oil (0.033 g, 63%).

Example 105: Preparation of (Z)-methylN-(2-isopropyl-5-methylphenyl)-N′-((4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamoyl)carbamimidothioate(FB65)

ToN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) (0.15 g, 0.26 mmol) and sodium acetate (0.053 g, 0.65 mmol)in ethanol (1 mL) was added iodomethane (0.020 mL, 0.32 mmol). Thereaction was stirred at room temperature overnight. The reaction mixturewas diluted with water and the water was decanted off to leave whitesolid, which was dried under vacuum for 3 hours. Purification by flashcolumn chromatography using 0-100% ethyl acetate/B, where B=1:1dichloromethane/hexanes, as eluent provided the title compound as aclear oil (0.081 g, 49%).

The following compounds were prepared in accordance to the procedure inExample 105.

Preparation of (Z)-ethylN-(2-isopropyl-5-methylphenyl)-N-((4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamoyl)carbamimidothioate(FB66)

The title compound was prepared as described in Example 105 usingN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) and iodoethane, purified by reverse-phase flash columnchromatography using 0-100% acetonitrile/water as eluent, and isolatedas a clear oil (0.050 g, 43%).

Example 106: Preparation of(Z)-1-(3-(2-isopropyl-5-methylphenyl)-5,5-dimethyl-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB68)

To a dry 2 dram vial equipped with magnetic stirrer was added(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5) (0.10 g, 0.16 mmol) and anhydrous dimethylformamide (0.5 mL). Tothis solution was added sodium hydride (60% oil dispersion, 0.0064 g,0.16 mmol) followed by iodomethane (0.022 g, 0.16 mmol). The reactionwas stirred overnight at room temperature. Purification by flash columnchromatography using 0-100% ethyl acetate/hexanes as eluent provided thetitle compound as a pale yellow foam (0.054 g, 52%).

The following compounds were prepared in accordance to the procedure inExample 106.

Preparation of(Z)-1-(6-(2-isopropyl-5-methylphenyl)-7-oxo-4-thia-6-azaspiro[2.4]heptan-5-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB69)

The title compound was prepared as described in Example 106 usingN-[5-methyl-2-isopropylphenyl]-N′-[2-(4-{1-[4-(trifluoromethoxy)-phenyl]-1H-1,2,4-triazol-3-yl}phenyl)ethyl]dicarbonimidothioicdiamide (F3) and 1,2-dibromoethane and isolated as a white foam (0.023g, 22%).

Example 107: Preparation of(Z)-1-(5-bromo-3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB70)

To a dry 2 dram vial equipped with magnetic stirrer was added(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5) (0.20 g, 0.32 mmol) and anhydrous dichloromethane (0.5 mL). To thissolution was added bromine (0.033 mL, 0.64 mmol). The reaction wasstirred overnight at room temperature. Purification by flash columnchromatography using 0-100% ethyl acetate/hexanes as eluent provided thetitle compound as a clear colorless oil (0.041 g, 18%).

Example 108: Preparation of(Z)-1-(2-bromo-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethyl)-3-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)urea(FB71)

To a dry round-bottomed flask (20 mL) equipped with a magnetic stirrerand a reflux condenser were added(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5) (0.20 g, 0.32 mmol), carbon tetrachloride (1 mL),N-bromosuccinimide (0.057 g, 0.32 mmol), and azobisisobutyronitrile(0.0053 g, 0.032 mmol). The reaction was heated to reflux for 2 hours.The reaction was cooled. Purification by flash column chromatographyusing 0-100% ethyl acetate/hexanes as eluent provided the title compoundas a yellow oil (0.049 g, 21%).

Example 109: Preparation of(Z)-1-(5-(2-hydroxypropan-2-yl)-3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(FB72)

To(Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea(F5) (0.40 g, 0.64 mmol) in acetone (30 mL) was added saturated aqueoussodium bicarbonate (3 mL). The reaction was heated to reflux for 12hours, cooled, and concentrated. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was dried andconcentrated. Purification by flash column chromatography using 100-40%A/B, where A=1:1 dichloromethane/hexanes and B=3:1 ethylacetate/acetone, as eluent provided the title compound as a white solid(0.095 g, 19%).

Using the procedures disclosed herein the following list of propheticmolecules having a structure according to Formula One may be made (TableP-One).

TABLE P-One P1

P2

P3

P4

P5

P6

P7

P8

P9

P10

P11

P12

P13

P14

P15

P16

P17

P18

P19

P20

P21

P22

P23

P24

P25

P26

P27

P28

P29

P30

P31

P32

P33

P34

P35

P36

P37

P38

P39

P40

P41

P42

P43

P44

P45

P46

P47

P48

P49

P50

P51

P52

P53

P54

P55

P56

P57

P58

P59

P60

P61

P62

P63

P64

P65

P66

P67

P68

P69

P70

P71

P72

P73

P74

P75

P76

P77

P78

P79

P80

P81

P82

P83

P84

P85

P86

P87

P88

P89

P90

P91

P92

P93

P94

P95

P96

P97

P98

P99

P100

P101

P102

P103

P104

P105

P106

P107

P108

P109

P110

P111

P112

P113

P114

P115

P116

P117

P118

P119

P120

P121

P122

P123

P124

P125

P126

P127

P128

P129

P130

P131

P132

P133

P134

P135

P136

P137

P138

P139

P140

P141

P142

P143

P144

P145

P146

P147

P148

P149

P150

P151

P152

P153

P154

P155

P156

P157

P158

P159

P160

P161

P162

P163

P164

P165

P166

P167

P168

P169

P170

P171

P172

P173

P174

P175

P176

P177

P178

P179

P180

P181

P182

P183

P184

P185

P186

P187

P188

P189

190

P191

P192

P193

P194

P195

Additionally using the procedures disclosed herein the following list ofprophetic molecules having a structure according to Formula One may bemade (Table P-Two).

TABLE P-TWO

P196

P197

P198

P199

P200

P201

P202

P203

P204

P205

P206

P207

P208

P209

P210

P211

P212

P213

P214

P215

P216

P217

P218

P219

P220

P221

P222

P223

P224

P225

P226

P227

P228

P229

P230

P231

P232

P233

P234

P235

P236

P237

P238

P239

P240

P241

P242

P243

P244

P245

P246

P247

P248

P249

P250

P251

P252

P253

P254

P255

P256

P257

P258

P259

P260

P261

P262

P263

P264

P265

P266

P267

P268

P269

P270

P271

P272

P273

P274

P275

P276

P277

P278

P279

P280

P281

P282

P283

P284

P285

P286

P287

P288

P289

P290

P291

P292

P293

P294

P295

P296

P297

P298

P299

P300

P301

P302

P303

P304

P305

P306

P307

P308

P309

P310

P311

P312

P313

P314

P315

P316

P317

P318

P319

P320

P321

P322

P323

P324

P325

P326

P327

P328

P329

P330

P331

P332

P333

P334

P335

P336

P337

P338

P339

P340

P341

P342

P343

P344

P345

P346

P347

P348

P349

P350

P351

P352

P353

P354

P355

P356

P357

P358

P359

P360

P361

P362

P363

P364

P365

P366

P367

P368

P369

P370

P371

P372

P373

P374

P375

P376

P377

P378

P379

P380

P381

P382

P383

P384

P385

P386

P387

P388

P389

P390

P391

P392

P393

P394

P395

P396

P397

P398

P399

P400

P401

P402

P403

P404

P405

P406

P407

P408

P409

P410

P411

P412

P413

P414

P415

P416

P417

P418

P419

P420

P421

P422

P423

P424

P425

P426

P427

P428

P429

P430

P431

P432

P433

P434

P435

P436

P437

P438

P439

P440

P441

P442

P443

P444

P445

P446

P447

P448

P449

P450

P451

P452

P453

P454

P455

P456

P457

P458

P459

P460

P461

P462

P463

P464

P465

P466

P467

P468

P469

P470

P471

P472

P473

P474

P475

P476

P477

P478

P479

P480

P481

P482

P483

P484

P485

P486

P487

P488

P489

P490

P491

P492

P493

P494

P495

P496

P497

P498

P499

P500

P501

P502

P503

P504

P505

P506

P507

P508

P509

P510

P511

P512

P513

P514

P515

P516

P517

P518

P519

P520

P521

P522

P523

P524

P525

P526

P527

P528

P529

P530

P531

P532

P533

P534

P535

P536

P537

P538

P539

P540

P541

P542

P543

P544

P545

P546

P547

P548

P549

P550

P551

P552

P553

P554

P555

P556

P557

P558

P559

P560

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Example A: Bioassays on Beet Armyworm (Spodoptera exigua) (“BAW”) andCabbage Looper (Trichoplusia ni) (“CL”)

BAW has few effective parasites, diseases, or predators to lower itspopulation. BAW infests many weeds, trees, grasses, legumes, and fieldcrops. In various places, it is of economic concern upon asparagus,cotton, corn, soybeans, tobacco, alfalfa, sugar beets, peppers,tomatoes, potatoes, onions, peas, sunflowers, and citrus, among otherplants. The Cabbage Looper is a member of the moth family Noctuidae. Itis found throughout the world. It is attacks cabbage, cauliflower,broccoli, Brussel sprouts, tomatoes, cucumbers, potatoes, kale, turnips,mustard, peppers, eggplant, watermelons, melons, squash, cantaloupe,peas, beans, collards, lettuce, spinach, celery, parsley, beets, peas,alfalfa, soybeans, and cotton. This species is very destructive toplants due to its voracious consumption of leaves. In the case ofcabbage, however, they feed not only on the wrapper leaves, but also maybore into the developing head. The larvae consume three times theirweight in plant material daily. The feeding sites are marked by largeaccumulations of sticky, wet fecal material.

Consequently, because of the above factors control of these pests isimportant. Furthermore, molecules that control these pests (BAW and CL),which are known as chewing pests, are useful in controlling other peststhat chew on plants.

Certain molecules disclosed in this document were tested against BAW andCEW using procedures described in the following examples. In thereporting of the results, the “BAW & CL Rating Table” was used (SeeTable Section).

Bioassays on BAW

Bioassays on BAW were conducted using a 128-well diet tray assay. one tofive second instar BAW larvae were placed in each well (3 mL) of thediet tray that had been previously filled with 1 mL of artificial dietto which 50 μg/cm² of the test compound (dissolved in 50 μL of 90:10acetone-water mixture) had been applied (to each of eight wells) andthen allowed to dry. Trays were covered with a clear self-adhesive coverand held at 25° C., 14:10 light-dark for five to seven days. Percentmortality was recorded for the larvae in each well; activity in theeight wells was then averaged. The results are indicated in the tableentitled “Table ABC: Biological Results” (See Table Section).

Bioassays on Cabbage Looper in CL

Bioassays on CL were conducted using a 128-well diet tray assay. one tofive second instar CL larvae were placed in each well (3 mL) of the diettray that had been previously filled with 1 mL of artificial diet towhich 50 μg/cm² of the test compound (dissolved in 50 μL of 90:10acetone-water mixture) had been applied (to each of eight wells) andthen allowed to dry. Trays were covered with a clear self-adhesive coverand held at 25° C., 14:10 light-dark for five to seven days. Percentmortality was recorded for the larvae in each well; activity in theeight wells was then averaged. The results are indicated in the tableentitled “Table ABC: Biological Results” (See Table Section).

Example B: Bioassays on Green Peach Aphid (“GPA”) (Myzus persicae)

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of the leaves, and the death of various tissues. Itis also hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, andzucchini, among other plants. GPA also attacks many ornamental cropssuch as carnation, chrysanthemum, flowering white cabbage, poinsettia,and roses. GPA has developed resistance to many pesticides.Consequently, because of the above factors control of this pest isimportant. Furthermore, molecules that control this pest (GPA), which isknown as a sucking pest, are useful in controlling other pests that suckon plants.

Certain molecules disclosed in this document were tested against GPAusing procedures described in the following example. In the reporting ofthe results, the “GPA Rating Table” was used (See Table Section).

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-50 GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four pots with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testcompound. The stock solutions were diluted 5× with 0.025% Tween 20 inwater to obtain the solution at 200 ppm test compound. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofcabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume ofacetone/methanol (1:1) solvent. Treated plants were held in a holdingroom for three days at approximately 25° C. and ambient relativehumidity (RH) prior to grading. Evaluation was conducted by counting thenumber of live aphids per plant under a microscope. Percent Control wasmeasured by using Abbott's correction formula (W. S. Abbott, “A Methodof Computing the Effectiveness of an Insecticide” J. Econ. Entomol. 18(1925), pp. 265-267) as follows.Corrected % Control=100*(X−Y)/X

-   -   where    -   X=No. of live aphids on solvent check plants and    -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table ABC: BiologicalResults” (See Table Section).

Example C: Bioassays on Yellow Fever Mosquito “YFM” (Aedes aegypti)

YFM prefers to feed on humans during the daytime and is most frequentlyfound in or near human habitations. YFM is a vector for transmittingseveral diseases. It is a mosquito that can spread the dengue fever andyellow fever viruses. Yellow fever is the second most dangerousmosquito-borne disease after malaria. Yellow fever is an acute viralhemorrhagic disease and up to 50% of severely affected persons withouttreatment will die from yellow fever. There are an estimated 200,000cases of yellow fever, causing 30,000 deaths, worldwide each year.Dengue fever is a nasty, viral disease; it is sometimes called“breakbone fever” or “break-heart fever” because of the intense pain itcan produce. Dengue fever kills about 20,000 people annually.Consequently, because of the above factors control of this pest isimportant. Furthermore, molecules that control this pest (YFM), which isknown as a sucking pest, are useful in controlling other pests thatcause human and animal suffering.

Certain molecules disclosed in this document were tested against YFMusing procedures described in the following paragraph. In the reportingof the results, the “YFM Rating Table” was used (See Table Section).

Master plates containing 400 μg of a molecule dissolved in 100 μL ofdimethyl sulfoxide (DMSO) (equivalent to a 4000 ppm solution) are used.A master plate of assembled molecules contains 15 μL per well. To thisplate, 135 μL of a 90:10 water:acetone mixture is added to each well. Arobot (Biomek® NXP Laboratory Automation Workstation) is programmed todispense 15 μL aspirations from the master plate into an empty 96-wellshallow plate (“daughter” plate). There are 6 reps (“daughter” plates)created per master. The created daughter plates are then immediatelyinfested with YFM larvae.

The day before plates are to be treated, mosquito eggs are placed inMillipore water containing liver powder to begin hatching (4 g. into 400mL). After the daughter plates are created using the robot, they areinfested with 220 μL of the liver powder/larval mosquito mixture (about1 day-old larvae). After plates are infested with mosquito larvae, anon-evaporative lid is used to cover the plate to reduce drying. Platesare held at room temperature for 3 days prior to grading. After 3 days,each well is observed and scored based on mortality.

The results are indicated in the table entitled “Table ABC: BiologicalResults” (See Table Section).

Agriculturally Acceptable Acid Addition Salts, Salt Derivatives,Solvates, Ester Derivatives, Polymorphs, Isotopes, and Radionuclides

Molecules of Formula One may be formulated into agriculturallyacceptable acid addition salts. By way of a non-limiting example, anamine function can form salts with hydrochloric, hydrobromic, sulfuric,phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric,oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic,aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic,hydroxyl-methanesulfonic, and hydroxyethanesulfonic acids. Additionally,by way of a non-limiting example, an acid function can form saltsincluding those derived from alkali or alkaline earth metals and thosederived from ammonia and amines. Examples of preferred cations includesodium, potassium, and magnesium.

Molecules of Formula One may be formulated into salt derivatives. By wayof a non-limiting example, a salt derivative can be prepared bycontacting a free base with a sufficient amount of the desired acid toproduce a salt. A free base may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous sodiumhydroxide, potassium carbonate, ammonia, and sodium bicarbonate. As anexample, in many cases, a pesticide, such as 2,4-D, is made morewater-soluble by converting it to its dimethylamine salt.

Molecules of Formula One may be formulated into stable complexes with asolvent, such that the complex remains intact after the non-complexedsolvent is removed. These complexes are often referred to as “solvates.”However, it is particularly desirable to form stable hydrates with wateras the solvent.

Molecules of Formula One may be made into ester derivatives. These esterderivatives can then be applied in the same manner as the moleculesdisclosed in this document is applied.

Molecules of Formula One may be made as various crystal polymorphs.Polymorphism is important in the development of agrochemicals sincedifferent crystal polymorphs or structures of the same molecule can havevastly different physical properties and biological performances.

Molecules of Formula One may be made with different isotopes. Ofparticular importance are molecules having ²H (also known as deuterium)in place of ¹H.

Molecules of Formula One may be made with different radionuclides. Ofparticular importance are molecules having ¹⁴C.

Stereoisomers

Molecules of Formula One may exist as one or more stereoisomers. Thus,certain molecules can be produced as racemic mixtures. It will beappreciated by those skilled in the art that one stereoisomer may bemore active than the other stereoisomers. Individual stereoisomers maybe obtained by known selective synthetic procedures, by conventionalsynthetic procedures using resolved starting materials, or byconventional resolution procedures. Certain molecules disclosed in thisdocument can exist as two or more isomers. The various isomers includegeometric isomers, diastereomers, and enantiomers. Thus, the moleculesdisclosed in this document include geometric isomers, racemic mixtures,individual stereoisomers, and optically active mixtures. It will beappreciated by those skilled in the art that one isomer may be moreactive than the others. The structures disclosed in the presentdisclosure are drawn in only one geometric form for clarity, but areintended to represent all geometric forms of the molecule.

Combinations

In another embodiment, molecules of Formula One may be used incombination (such as, in a compositional mixture, or a simultaneous orsequential application) with one or more compounds each having a mode ofaction that is the same as, similar to, or different from, the mode ofaction (“MoA”) of the molecules of Formula One. Modes of action include,for example the following: Acetylcholinesterase (AChE) inhibitors;GABA-gated chloride channel antagonists; Sodium channel modulators;Nicotinic acetylcholine (nAChR) agonists; Nicotinic acetylcholinereceptor (nAChR) allosteric activators; Chloride channel activators;Juvenile hormone mimics; Miscellaneous non-specific (multi-site)inhibitors; Selective homopteran feeding blockers; Mite growthinhibitors; Microbial disruptors of insect midgut membranes; Inhibitorsof mitochondrial ATP synthase; Uncouplers of oxidative phosphorylationvia disruption of the proton gradient; Nicotinic acetylcholine receptor(nAChR) channel blockers; Inhibitors of chitin biosynthesis, type 0;Inhibitors of chitin biosynthesis, type 1; Moulting disruptor, Dipteran;Ecdysone receptor agonists; Octopamine receptor agonists; Mitochondrialcomplex III electron transport inhibitors; Mitochondrial complex Ielectron transport inhibitors; Voltage-dependent sodium channelblockers; Inhibitors of acetyl CoA carboxylase; Mitochondrial complex IVelectron transport inhibitors; Mitochondrial complex II electrontransport inhibitors; and Ryanodine receptor modulators.

In another embodiment, molecules of Formula One may be used incombination (such as, in a compositional mixture, or a simultaneous orsequential application) with one or more compounds having acaricidal,algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal,molluscicidal, nematicidal, rodenticidal, and/or virucidal properties.

In another embodiment, the molecules of Formula One may be used incombination (such as, in a compositional mixture, or a simultaneous orsequential application) with one or more compounds that areantifeedants, bird repellents, chemosterilants, herbicide safeners,insect attractants, insect repellents, mammal repellents, matingdisrupters, plant activators, plant growth regulators, and/orsynergists.

In another embodiment, the molecules of Formula One may be used incombination (such as, in a compositional mixture, or a simultaneous orsequential application) with one or more of the followingcompounds—(3-ethoxypropyl)mercury bromide, 1,2-dichloropropane,1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol,2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA,2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium,2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl,2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl,2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl,2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium,2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D,2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl,2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium,2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl,2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium,2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl,2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl,2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl,2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium,2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium,2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP,2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP,4-aminopyridine, 4-CPA, 4-CPA-diolamine, 4-CPA-potassium, 4-CPA-sodium,4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate,8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate,acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole,acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl,acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein,acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc,afidopyropen, alachlor, alanycarb, albendazole, aldicarb, aldimorph,aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin,alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac,alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione,ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet,amidosulfuron, aminocarb, aminocyclopyrachlor,aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid,aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium,amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate,amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate,amobam, ampropylfos, anabasine, anabasine sulfate, ancymidol, anilazine,anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenousoxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium,athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycinehydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos,azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram,azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban,barium hexafluorosilicate, barium polysulfide, barthrin, BCPC,beflubutamid, benalaxyl, benalaxyl-M, benazolin,benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium,bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb,benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox,bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron,bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl,benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkoniumchloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone,benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid,benzovindiflupyr, benzoximate, benzoylprop, benzoylprop-ethyl,benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberinechloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone,bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos,bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin,bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir,bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol,bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid,boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum,brofenvalerate, brofluthrinate, bromacil, bromacil-lithium,bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos,bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT,bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil,bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxyniloctanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol,bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundymixture, busulfan, butacarb, butachlor, butafenacil, butamifos,butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron,butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin,butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos,cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide,calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor,captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam,carbendazim, carbendazim benzenesulfonate, carbendazim sulfite,carbetamide, carbofuran, carbon disulfide, carbon tetrachloride,carbophenothion, carbosulfan, carboxazole, carboxide, carboxin,carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartaphydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure,Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone,chlomethoxyfen, chloralose, chloramben, chloramben-ammonium,chloramben-diolamine, chloramben-methyl, chloramben-methylammonium,chloramben-sodium, chloramine phosphorus, chloramphenicol,chloraniformethan, chloranil, chloranocryl, chlorantraniliprole,chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside,chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane,chlordecone, chlordimeform, chlordimeform hydrochloride,chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac,chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole,chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide,chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren,chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon,chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequatchloride, chlornidine, chlornitrofen, chlorobenzilate,chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron,chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin,chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron,chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim,chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos,chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal,chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos,chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II,cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide,cisanilide, cismethrin, clacyfos, clethodim, climbazole, cliodinate,clodinafop, clodinafop-propargyl, cloethocarb, clofencet,clofencet-potassium, clofentezine, clofibric acid, clofop,clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid,clopyralid-methyl, clopyralid-olamine, clopyralid-potassium,clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet,cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel,clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA,codlelure, colophonate, copper acetate, copper acetoarsenite, copperarsenate, copper carbonate, basic, copper hydroxide, copper naphthenate,copper oleate, copper oxychloride, copper silicate, copper sulfate,copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl,coumithoate, coumoxystrobin, coumoxystrobin, CPMC, CPMF, CPPC,credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate,cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide,curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos,cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid,cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate,cycloprothrin, cyclopyrimorate, cyclosulfamuron, cycloxydim, cycluron,cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop,cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazolehydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin,cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole,cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide,cyromazine, cythioate, daimuron, dalapon, dalapon-calcium,dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet,dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin,decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion,demephion-O, demephion-S, demeton, demeton-methyl, demeton-O,demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon,desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos,di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate,dibutyl succinate, dicamba, dicamba-diglycolamine,dicamba-dimethylammonium, dicamba-diolamine, dicamba-isopropylammonium,dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium,dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion,dichlofluanid, dichlone, dichloralurea, dichlorbenzuron,dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid,dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl,dichlorprop-butotyl, dichlorprop-dimethylammonium,dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl,dichlorprop-P, dichlorprop-P-2-ethylhexyl,dichlorprop-P-dimethylammonium, dichlorprop-potassium,dichlorprop-P-potassium, dichlorprop-P-sodium, dichlorprop-sodium,dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop,diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam,dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon,dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl,diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate,diethyltoluamide, difenacoum, difenoconazole, difenopenten,difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate,difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr,diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor,dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone,dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid,dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph,dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos,dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine,dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton,dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton,dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium,dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon,dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan,dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium,diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn,dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram,disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos,dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium,DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorphbenzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine,dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP,EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin,emamectin benzoate, EMPC, empenthrin, endosulfan, endothal,endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion,endrin, enestroburin, enoxastrobin, EPN, epocholeone, epofenonane,epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol,erlujixiancaoan, esdepallethrine, esfenvalerate, esprocarb, etacelasil,etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin,ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon,ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole,ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos,ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate,ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylenedibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercurybromide, ethylmercury chloride, ethylmercury phosphate, etinofen,etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos,eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf,fenaminstrobin, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor,fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole,fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin,fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb,fenoprop, fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl,fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium,fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl,fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb,fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph,fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium,fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop,fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate,fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron,fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil,flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl,flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen,flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop,fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl,fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine,flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin,flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil,fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron,flufenoxystrobin, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole,flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac,flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron,fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide,fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide,fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin,flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium,flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl,flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol,flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr,fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid,flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl,flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad,fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron,forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride,formothion, formparanate, formparanate hydrochloride, fosamine,fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate,fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi,funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin,furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis,furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen,gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins,gliftor, glufosinate, glufosinate-ammonium, glufosinate-P,glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime,glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium,glyphosate-isopropylammonium, glyphosate-monoammonium,glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium,glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatineacetates, halacrinate, halauxifen, halauxifen-methyl, halfenprox,halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine,haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P,haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel,hempa, HEOD, heptachlor, heptafluthrin, heptenophos, heptopargil,herbimycin, heterophos, hexachloroacetone, hexachlorobenzene,hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron,hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox,HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon,hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol,hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalilsulfate, imazamethabenz, imazamethabenz-methyl, imazamox,imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr,imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium,imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium,imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz,iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate,imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin,iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl,iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium,ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine,ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb,iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan,isocarbamid, isocarbophos, isocil, isodrin, isofenphos,isofenphos-methyl, isofetamid, isolan, isomethiozin, isonoruron,isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon,isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione,isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole,isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins,jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong,jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos,juvenile hormone I, juvenile hormone II, juvenile hormone III,kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin,kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox,ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi,lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil,lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure,looplure, lufenuron, Ivdingjunzhi, Ivxiancaolin, lythidathion, MAA,malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper,mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA,MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium,MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl,MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl,MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil,mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl,mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl,mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl,mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium,mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform,medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr,mefenpyr-diethyl, mefluidide, mefluidide-diolamine,mefluidide-potassium, megatomoic acid, menazon, mepanipyrim,meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride,mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride,mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron,mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone,metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop,metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron,metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron,methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole,methfuroxam, methidathion, methiobencarb, methiocarb,methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos,methometon, methomyl, methoprene, methoprotryne, methoquin-butyl,methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methylapholate, methyl bromide, methyl eugenol, methyl iodide, methylisothiocyanate, methylacetophos, methylchloroform, methyldymron,methylene chloride, methylmercury benzoate, methylmercury dicyandiamide,methylmercury pentachlorophenoxide, methylneodecanamide, metiram,metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb,metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone,metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos,mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox,mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron,monochloroacetic acid, monocrotophos, monolinuron, monosulfuron,monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquatdichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid,moxidectin, MSMA, muscalure, myclobutanil, myclozolin,N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled,naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyaceticacids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin,neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine,nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin,nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl,norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron,nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace,omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron,oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil,oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon,oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxathiapiprolin,oxaziclomefone, oxine-copper, oxolinic acid, oxpoconazole, oxpoconazolefumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton,oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride,paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat,paraquat dichloride, paraquat dimetilsulfate, parathion,parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid,penconazole, pencycuron, pendimethalin, penflufen, penfluron,penoxsulam, pentachlorophenol, pentachlorophenyl laurate, pentanochlor,penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin,pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin,phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate,phenylmercury chloride, phenylmercury derivative of pyrocatechol,phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim,phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet,phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin,phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl,picloram-isoctyl, picloram-methyl, picloram-olamine, picloram-potassium,picloram-triethylammonium, picloram-tris(2-hydroxypropyl)ammonium,picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden,piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos,piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb,pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate,polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan,potassium arsenite, potassium azide, potassium cyanate, potassiumgibberellate, potassium naphthenate, potassium polysulfide, potassiumthiocyanate, potassium α-naphthaleneacetate, pp′-DDT, prallethrin,precocene I, precocene II, precocene III, pretilachlor, primidophos,primisulfuron, primisulfuron-methyl, probenazole, prochloraz,prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine,profenofos, profluazol, profluralin, profluthrin, profoxydim,proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium,prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit,propachlor, propamidine, propamidine dihydrochloride, propamocarb,propamocarb hydrochloride, propanil, propaphos, propaquizafop,propargite, proparthrin, propazine, propetamphos, propham,propiconazole, propineb, propisochlor, propoxur, propoxycarbazone,propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide,proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron,prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole,prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor,pydanon, pyflubumide, pymetrozine, pyracarbolid, pyraclofos, pyraclonil,pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat,pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate,pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion,pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins,pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim,pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl,pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon,pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl,pyriminostrobin, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone,pyriprole, pyripropanol, pyriproxyfen, pyrisoxazole, pyrithiobac,pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam,pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate,quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole,quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos,quintozene, quizalofop, quizalofop-ethyl, quizalofop-P,quizalofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding,rabenzazole, rafoxanide, rebemide, rescalure, resmethrin, rhodethanil,rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania,saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine,santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane,selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin,sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane,silica gel, silthiofam, simazine, simeconazole, simeton, simetryn,sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodiumchlorate, sodium fluoride, sodium fluoroacetate, sodiumhexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide,sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate,sodium α-naphthaleneacetate, sophamide, spinetoram, spinosad,spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin,streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron,sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram,sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep,sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfurylfluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate,tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl,TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide,tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron,tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin,tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim,terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton,terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane,tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin,tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate,thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid,thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr,thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone,thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl,thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam,thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper,thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon,thionazin, thiophanate, thiophanate-methyl, thioquinox,thiosemicarbazide, thiosultap, thiosultap-diammonium,thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram,thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid,tirpate, tolclofos-methyl, tolfenpyrad, tolprocarb, tolylfluanid,tolylmercury acetate, topramezone, tralkoxydim, tralocythrin,tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine,triacontanol, triadimefon, triadimenol, triafamone, tri-allate,triamiphos, triapenthenol, triarathene, triarimol, triasulfuron,triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron,tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide,trichlorfon, trichlormetaphos-3, trichloronat, triclopyr,triclopyr-butotyl, triclopyr-ethyl, triclopyricarb,triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane,trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron,trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin,triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl,trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb,trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan,triptolide, tritac, triticonazole, tritosulfuron, trunc-call,uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin,valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate,vinclozolin, warfarin, warfarin-potassium, warfarin-sodium,xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols,xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin,zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram,zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, α-ecdysone,α-multistriatin, and α-naphthaleneacetic acid. For more informationconsult the “COMPENDIUM OF PESTICIDE COMMON NAMES” located athttp://www.alanwood.net/pesticides/index.html. Also consult “THEPESTICIDE MANUAL” 15th Edition, edited by C D S Tomlin, copyright 2009by British Crop Production Council, or its prior, or more recenteditions.

In another embodiment, molecules of Formula One may also be used incombination (such as in a compositional mixture, or a simultaneous orsequential application) with one or more biopesticides. The term“biopesticide” is used for microbial biological pest control agents thatare applied in a similar manner to chemical pesticides. Commonly theseare bacterial, but there are also examples of fungal control agents,including Trichoderma spp. and Ampelomyces quisqualis (a control agentfor grape powdery mildew). Bacillus subtilis are used to control plantpathogens. Weeds and rodents have also been controlled with microbialagents. One well-known insecticide example is Bacillus thuringiensis, abacterial disease of Lepidoptera, Coleoptera, and Diptera. Because ithas little effect on other organisms, it is considered moreenvironmentally friendly than synthetic pesticides. Biologicalinsecticides include products based on: entomopathogenic fungi (e.g.Metarhizium anisopliae); entomopathogenic nematodes (e.g. Steinernemafeltiae); and entomopathogenic viruses (e.g. Cydia pomonellagranulovirus).

Other examples of entomopathogenic organisms include, but are notlimited to, baculoviruses, bacteria and other prokaryotic organisms,fungi, protozoa and Microsproridia. Biologically derived insecticidesinclude, but not limited to, rotenone, veratridine, as well as microbialtoxins; insect tolerant or resistant plant varieties; and organismsmodified by recombinant DNA technology to either produce insecticides orto convey an insect resistant property to the genetically modifiedorganism. In one embodiment, the molecules of Formula One may be usedwith one or more biopesticides in the area of seed treatments and soilamendments. The Manual of Biocontrol Agents gives a review of theavailable biological insecticide (and other biology-based control)products. Copping L. G. (ed.) (2004). The Manual of Biocontrol Agents(formerly the Biopesticide Manual) 3rd Edition. British Crop ProductionCouncil (BCPC), Farnham, Surrey UK.

In another embodiment, the above possible combinations may be used in awide variety of weight ratios. For example, a two component mixture, theweight ratio of a molecule of Formula One to another compound, can befrom about 100:1 to about 1:100; in another example the weight ratio canbe about 50:1 to about 1:50; in another example the weight ratio can beabout 20:1 to about 1 to 20; in another example the weight ratio can beabout 10:1 to about 1:10; in another example the weight ratio can beabout 5:1 to 1:5; in another example the weight ratio can be about 3:1to about 1:3; and in a final example the weight ratio can be about 1:1.However, preferably, weight ratios less than about 10:1 to about 1:10are preferred. It is also preferred sometimes to use a three or fourcomponent mixture comprising one or more molecules of Formula One andone or more other compounds from the above possible combinations.

Formulations

A pesticide is rarely suitable for application in its pure form. It isusually necessary to add other substances so that the pesticide can beused at the required concentration and in an appropriate form,permitting ease of application, handling, transportation, storage, andmaximum pesticide activity. Thus, pesticides are formulated into, forexample, baits, concentrated emulsions, dusts, emulsifiableconcentrates, fumigants, gels, granules, microencapsulations, seedtreatments, suspension concentrates, suspoemulsions, tablets, watersoluble liquids, water dispersible granules or dry flowables, wettablepowders, and ultra-low volume solutions. For further information onformulation types see “Catalogue of Pesticide Formulation Types andInternational Coding System” Technical Monograph n^(o)2, 5th Edition byCropLife International (2002).

Pesticides are applied most often as aqueous suspensions or emulsionsprepared from concentrated formulations of such pesticides. Suchwater-soluble, water-suspendable, or emulsifiable formulations areeither solids, usually known as wettable powders, or water dispersiblegranules, or liquids usually known as emulsifiable concentrates, oraqueous suspensions. Wettable powders, which may be compacted to formwater dispersible granules, comprise an intimate mixture of thepesticide, a carrier, and surfactants. The concentration of thepesticide is usually from about 10% to about 90% by weight. The carrieris usually selected from among the attapulgite clays, themontmorillonite clays, the diatomaceous earths, or the purifiedsilicates. Effective surfactants, comprising from about 0.5% to about10% of the wettable powder, are found among sulfonated lignins,condensed naphthalenesulfonates, naphthalenesulfonates,alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants suchas ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of pesticides comprise a convenientconcentration of a pesticide, such as from about 50 to about 500 gramsper liter of liquid dissolved in a carrier that is either a watermiscible solvent or a mixture of water-immiscible organic solvent andemulsifiers. Useful organic solvents include aromatics, especiallyxylenes and petroleum fractions, especially the high-boilingnaphthalenic and olefinic portions of petroleum such as heavy aromaticnaphtha. Other organic solvents may also be used, such as the terpenicsolvents including rosin derivatives, aliphatic ketones such ascyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitableemulsifiers for emulsifiable concentrates are selected from conventionalanionic and non-ionic surfactants.

Aqueous suspensions comprise suspensions of water-insoluble pesticidesdispersed in an aqueous carrier at a concentration in the range fromabout 5% to about 50% by weight. Suspensions are prepared by finelygrinding the pesticide and vigorously mixing it into a carrier comprisedof water and surfactants. Ingredients, such as inorganic salts andsynthetic or natural gums may also be added, to increase the density andviscosity of the aqueous carrier. It is often most effective to grindand mix the pesticide at the same time by preparing the aqueous mixtureand homogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

Pesticides may also be applied as granular compositions that areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the pesticide,dispersed in a carrier that comprises clay or a similar substance. Suchcompositions are usually prepared by dissolving the pesticide in asuitable solvent and applying it to a granular carrier which has beenpre-formed to the appropriate particle size, in the range of from about0.5 to about 3 mm. Such compositions may also be formulated by making adough or paste of the carrier and compound and crushing and drying toobtain the desired granular particle size.

Dusts containing a pesticide are prepared by intimately mixing thepesticide in powdered form with a suitable dusty agricultural carrier,such as kaolin clay, ground volcanic rock, and the like. Dusts cansuitably contain from about 1% to about 10% of the pesticide. They canbe applied as a seed dressing or as a foliage application with a dustblower machine.

It is equally practical to apply a pesticide in the form of a solutionin an appropriate organic solvent, usually petroleum oil, such as thespray oils, which are widely used in agricultural chemistry.

Pesticides can also be applied in the form of an aerosol composition. Insuch compositions the pesticide is dissolved or dispersed in a carrier,which is a pressure-generating propellant mixture. The aerosolcomposition is packaged in a container from which the mixture isdispensed through an atomizing valve.

Pesticide baits are formed when the pesticide is mixed with food or anattractant or both. When the pests eat the bait they also consume thepesticide. Baits may take the form of granules, gels, flowable powders,liquids, or solids. They can be used in pest harborages.

Fumigants are pesticides that have a relatively high vapor pressure andhence can exist as a gas in sufficient concentrations to kill pests insoil or enclosed spaces. The toxicity of the fumigant is proportional toits concentration and the exposure time. They are characterized by agood capacity for diffusion and act by penetrating the pest'srespiratory system or being absorbed through the pest's cuticle.Fumigants are applied to control stored product pests under gas proofsheets, in gas sealed rooms or buildings or in special chambers.

Pesticides can be microencapsulated by suspending the pesticideparticles or droplets in plastic polymers of various types. By alteringthe chemistry of the polymer or by changing factors in the processing,microcapsules can be formed of various sizes, solubility, wallthicknesses, and degrees of penetrability. These factors govern thespeed with which the active ingredient within is released, which inturn, affects the residual performance, speed of action, and odor of theproduct.

Oil solution concentrates are made by dissolving pesticide in a solventthat will hold the pesticide in solution. Oil solutions of a pesticideusually provide faster knockdown and kill of pests than otherformulations due to the solvents themselves having pesticidal action andthe dissolution of the waxy covering of the integument increasing thespeed of uptake of the pesticide. Other advantages of oil solutionsinclude better storage stability, better penetration of crevices, andbetter adhesion to greasy surfaces.

Another embodiment is an oil-in-water emulsion, wherein the emulsioncomprises oily globules which are each provided with a lamellar liquidcrystal coating and are dispersed in an aqueous phase, wherein each oilyglobule comprises at least one compound which is agriculturally active,and is individually coated with a monolamellar or oligolamellar layercomprising: (1) at least one non-ionic lipophilic surface-active agent,(2) at least one non-ionic hydrophilic surface-active agent and (3) atleast one ionic surface-active agent, wherein the globules having a meanparticle diameter of less than 800 nanometers. Further information onthe embodiment is disclosed in U.S. patent publication 20070027034published Feb. 1, 2007, having patent application Ser. No. 11/495,228.For ease of use, this embodiment will be referred to as “OIWE”.

For further information consult “Insect Pest Management” 2nd Edition byD. Dent, copyright CAB International (2000). Additionally, for moredetailed information consult “Handbook of Pest Control—The Behavior,Life History, and Control of Household Pests” by Arnold Mallis, 9thEdition, copyright 2004 by GIE Media Inc.

Other Formulation Components

Generally, when the molecules disclosed in Formula One are used in aformulation, such formulation can also contain other components. Thesecomponents include, but are not limited to, (this is a non-exhaustiveand non-mutually exclusive list) wetters, spreaders, stickers,penetrants, buffers, sequestering agents, drift reduction agents,compatibility agents, anti-foam agents, cleaning agents, andemulsifiers. A few components are described forthwith.

A wetting agent is a substance that when added to a liquid increases thespreading or penetration power of the liquid by reducing the interfacialtension between the liquid and the surface on which it is spreading.Wetting agents are used for two main functions in agrochemicalformulations: during processing and manufacture to increase the rate ofwetting of powders in water to make concentrates for soluble liquids orsuspension concentrates; and during mixing of a product with water in aspray tank to reduce the wetting time of wettable powders and to improvethe penetration of water into water-dispersible granules. Examples ofwetting agents used in wettable powder, suspension concentrate, andwater-dispersible granule formulations are: sodium lauryl sulfate;sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphaticalcohol ethoxylates.

A dispersing agent is a substance which adsorbs onto the surface ofparticles and helps to preserve the state of dispersion of the particlesand prevents them from reaggregating. Dispersing agents are added toagrochemical formulations to facilitate dispersion and suspension duringmanufacture, and to ensure the particles redisperse into water in aspray tank. They are widely used in wettable powders, suspensionconcentrates and water-dispersible granules. Surfactants that are usedas dispersing agents have the ability to adsorb strongly onto a particlesurface and provide a charged or steric barrier to reaggregation ofparticles. The most commonly used surfactants are anionic, non-ionic, ormixtures of the two types. For wettable powder formulations, the mostcommon dispersing agents are sodium lignosulfonates. For suspensionconcentrates, very good adsorption and stabilization are obtained usingpolyelectrolytes, such as sodium naphthalene sulfonate formaldehydecondensates. Tristyrylphenol ethoxylate phosphate esters are also used.Non-ionics such as alkylarylethylene oxide condensates and EO-PO blockcopolymers are sometimes combined with anionics as dispersing agents forsuspension concentrates. In recent years, new types of very highmolecular weight polymeric surfactants have been developed as dispersingagents. These have very long hydrophobic ‘backbones’ and a large numberof ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant.These high molecular weight polymers can give very good long-termstability to suspension concentrates because the hydrophobic backboneshave many anchoring points onto the particle surfaces. Examples ofdispersing agents used in agrochemical formulations are: sodiumlignosulfonates; sodium naphthalene sulfonate formaldehyde condensates;tristyrylphenol ethoxylate phosphate esters; aliphatic alcoholethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graftcopolymers.

An emulsifying agent is a substance which stabilizes a suspension ofdroplets of one liquid phase in another liquid phase. Without theemulsifying agent the two liquids would separate into two immiscibleliquid phases. The most commonly used emulsifier blends containalkylphenol or aliphatic alcohol with twelve or more ethylene oxideunits and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. Arange of hydrophile-lipophile balance (“HLB”) values from 8 to 18 willnormally provide good stable emulsions. Emulsion stability can sometimesbe improved by the addition of a small amount of an EO-PO blockcopolymer surfactant.

A solubilizing agent is a surfactant which will form micelles in waterat concentrations above the critical micelle concentration. The micellesare then able to dissolve or solubilize water-insoluble materials insidethe hydrophobic part of the micelle. The types of surfactants usuallyused for solubilization are non-ionics, sorbitan monooleates, sorbitanmonooleate ethoxylates, and methyl oleate esters.

Surfactants are sometimes used, either alone or with other additivessuch as mineral or vegetable oils as adjuvants to spray-tank mixes toimprove the biological performance of the pesticide on the target. Thetypes of surfactants used for bioenhancement depend generally on thenature and mode of action of the pesticide. However, they are oftennon-ionics such as: alkyl ethoxylates; linear aliphatic alcoholethoxylates; aliphatic amine ethoxylates.

A carrier or diluent in an agricultural formulation is a material addedto the pesticide to give a product of the required strength. Carriersare usually materials with high absorptive capacities, while diluentsare usually materials with low absorptive capacities. Carriers anddiluents are used in the formulation of dusts, wettable powders,granules and water-dispersible granules.

Organic solvents are used mainly in the formulation of emulsifiableconcentrates, oil-in-water emulsions, suspoemulsions, and ultra-lowvolume formulations, and to a lesser extent, granular formulations.Sometimes mixtures of solvents are used. The first main groups ofsolvents are aliphatic paraffinic oils such as kerosene or refinedparaffins. The second main group (and the most common) comprises thearomatic solvents such as xylene and higher molecular weight fractionsof C9 and C10 aromatic solvents. Chlorinated hydrocarbons are useful ascosolvents to prevent crystallization of pesticides when the formulationis emulsified into water. Alcohols are sometimes used as cosolvents toincrease solvent power. Other solvents may include vegetable oils, seedoils, and esters of vegetable and seed oils.

Thickeners or gelling agents are used mainly in the formulation ofsuspension concentrates, emulsions and suspoemulsions to modify therheology or flow properties of the liquid and to prevent separation andsettling of the dispersed particles or droplets. Thickening, gelling,and anti-settling agents generally fall into two categories, namelywater-insoluble particulates and water-soluble polymers. It is possibleto produce suspension concentrate formulations using clays and silicas.Examples of these types of materials, include, but are not limited to,montmorillonite, bentonite, magnesium aluminum silicate, andattapulgite. Water-soluble polysaccharides have been used asthickening-gelling agents for many years. The types of polysaccharidesmost commonly used are natural extracts of seeds and seaweeds or aresynthetic derivatives of cellulose. Examples of these types of materialsinclude, but are not limited to, guar gum; locust bean gum; carrageenam;alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC);hydroxyethyl cellulose (HEC). Other types of anti-settling agents arebased on modified starches, polyacrylates, polyvinyl alcohol andpolyethylene oxide. Another good anti-settling agent is xanthan gum.

Microorganisms can cause spoilage of formulated products. Thereforepreservation agents are used to eliminate or reduce their effect.Examples of such agents include, but are not limited to: propionic acidand its sodium salt; sorbic acid and its sodium or potassium salts;benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt;methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT).

The presence of surfactants often causes water-based formulations tofoam during mixing operations in production and in application through aspray tank. In order to reduce the tendency to foam, anti-foam agentsare often added either during the production stage or before fillinginto bottles. Generally, there are two types of anti-foam agents, namelysilicones and non-silicones. Silicones are usually aqueous emulsions ofdimethyl polysiloxane, while the non-silicone anti-foam agents arewater-insoluble oils, such as octanol and nonanol, or silica. In bothcases, the function of the anti-foam agent is to displace the surfactantfrom the air-water interface.

“Green” agents (e.g., adjuvants, surfactants, solvents) can reduce theoverall environmental footprint of crop protection formulations. Greenagents are biodegradable and generally derived from natural and/orsustainable sources, e.g. plant and animal sources. Specific examplesare: vegetable oils, seed oils, and esters thereof, also alkoxylatedalkyl polyglucosides.

For further information, see “Chemistry and Technology of AgrochemicalFormulations” edited by D. A. Knowles, copyright 1998 by Kluwer AcademicPublishers. Also see “Insecticides in Agriculture andEnvironment—Retrospects and Prospects” by A. S. Perry, I. Yamamoto, I.Ishaaya, and R. Perry, copyright 1998 by Springer-Verlag.

Pests

In general, the molecules of Formula One may be used to control pestse.g. ants, aphids, beetles, bristletails, cockroaches, crickets,earwigs, fleas, flies, grasshoppers, leafhoppers, lice, locusts, mites,moths, nematodes, scales, symphylans, termites, thrips, ticks, wasps,and whiteflies.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Phyla Nematoda and/or Arthropoda.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Classes of Arachnida, Symphyla, and/or Insecta.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Anoplura. A non-exhaustive list of particulargenera includes, but is not limited to, Haematopinus spp., Hoplopleuraspp., Linognathus spp., Pediculus spp., and Polyplax spp. Anon-exhaustive list of particular species includes, but is not limitedto, Haematopinus asini, Haematopinus suis, Linognathus setosus,Linognathus ovillus, Pediculus humanus capitis, Pediculus humanushumanus, and Pthirus pubis.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Order Coleoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Acanthoscelides spp.,Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophoraspp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp.,Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp.,Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyctus spp.,Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp.,Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp.,Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp.,and Tribolium spp. A non-exhaustive list of particular species includes,but is not limited to, Acanthoscelides obtectus, Agrilus planipennis,Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus,Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum,Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata,Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi,Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinisnitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestespusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporausmarginatus, Dermestes lardarius, Dermestes maculatus, Epilachnavarivestis, Faustinus cubae, Hylobius pales, Hypera postica,Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata,Liogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus,Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolonthamelolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros,Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus,Oulema oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanustruncatus, Rhyzopertha dominica, Sitona lineatus, Sitophilus granarius,Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Triboliumcastaneum, Tribolium confusum, Trogoderma variabile, and Zabrustenebrioides.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Dermaptera.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Blattaria. A non-exhaustive list ofparticular species includes, but is not limited to, Blattella germanica,Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana,Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa,Pycnoscelus surinamensis, and Supella longipalpa.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Diptera. A non-exhaustive list of particulargenera includes, but is not limited to, Aedes spp., Agromyza spp.,Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp.,Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineuraspp., Delia spp., Drosophila spp., Fannia spp., Hylemyia spp., Liriomyzaspp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. Anon-exhaustive list of particular species includes, but is not limitedto, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens,Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis,Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineurabrassicae, Delia platura, Fannia canicularis, Fannia scalaris,Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans,Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Muscaautumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomyabetae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletismendax, Sitodiplosis mosellana, and Stomoxys calcitrans.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Hemiptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Adelges spp.,Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastesspp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp.,Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp.,Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp.,Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphumspp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp.,Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive listof particular species includes, but is not limited to, Acrosternumhilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicusdispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula,Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi,Aulacorthum solani, Bemisia argentifolii, Bemisia tabaci, Blissusleucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicorynebrassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus,Cimex lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphisnoxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus,Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistusheros, Euschistus servus, Helopeltis antonii, Helopeltis theivora,Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus,Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus,Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium,Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarva frimbiolata,Metopolophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettixcinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvatalugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis,Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus,Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus,Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes,Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi,Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobionavenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodesabutiloneus, Unaspis yanonensis, and Zulia entrerriana.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Hymenoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Acromyrmex spp., Attaspp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp.,Neodiprion spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp.,Vespula spp., and Xylocopa spp. A non-exhaustive list of particularspecies includes, but is not limited to, Athalia rosae, Atta texana,Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis,Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsisrichtery, Solenopsis xyloni, and Tapinoma sessile.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Isoptera. A non-exhaustive list of particulargenera includes, but is not limited to, Coptotermes spp., Cornitermesspp., Cryptotermes spp., Heterotermes spp., Kalotermes spp.,Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermesspp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp.,and Zootermopsis spp. A non-exhaustive list of particular speciesincludes, but is not limited to, Coptotermes curvignathus, Coptotermesfrenchi, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi,Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermesflavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermessantonensis, Reticulitermes speratus, Reticulitermes tibialis, andReticulitermes virginicus.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Lepidoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Adoxophyes spp.,Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilospp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp.,Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp.,Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp.,Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Peridroma spp.,Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp.,Synanthedon spp., and Yponomeuta spp. A non-exhaustive list ofparticular species includes, but is not limited to, Achaea janata,Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana,Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella,Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archipsrosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes,Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposinaniponensis, Chlumetia transversa, Choristoneura rosaceana,Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydiacaryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydiapomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella,Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpuslignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella,Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoeciliaambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indicata,Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellulaundalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucopteracoffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotisalbicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti,Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta,Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata,Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemisheparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia,Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistiscitrella, Pieris rapae, Plathypena scabra, Plodia interpunctella,Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae,Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu,Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setoranitens, Sitotroga cerealella, Sparganothis pilleriana, Spodopteraexigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides,Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae,and Zeuzera pyrina.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Mallophaga. A non-exhaustive list ofparticular genera includes, but is not limited to, Anaticola spp.,Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp., andTrichodectes spp. A non-exhaustive list of particular species includes,but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis,Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas,Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Orthoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Melanoplus spp., andPterophylla spp. A non-exhaustive list of particular species includes,but is not limited to, Anabrus simplex, Gryllotalpa africana,Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla,Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, andScudderia furcata.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Siphonaptera. A non-exhaustive list ofparticular species includes, but is not limited to, Ceratophyllusgallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalidesfelis, and Pulex irritans.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Thysanoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Caliothrips spp.,Frankliniella spp., Scirtothrips spp., and Thrips spp. A non-exhaustivelist of particular sp. includes, but is not limited to, Frankliniellafusca, Frankliniella occidentalis, Frankliniella schultzei,Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothripscruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothripsrhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thripsorientalis, Thrips tabaci.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Thysanura. A non-exhaustive list ofparticular genera includes, but is not limited to, Lepisma spp. andThermobia spp.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Acarina. A non-exhaustive list of particulargenera includes, but is not limited to, Acarus spp., Aculops spp.,Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp.,Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp.,Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list ofparticular species includes, but is not limited to, Acarapis woodi,Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi,Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus,Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoidespteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychuscoffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi,Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalussanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychusurticae, and Varroa destructor.

In another embodiment, the molecules of Formula One may be used tocontrol pest of the Order Symphyla. A non-exhaustive list of particularsp. includes, but is not limited to, Scutigerella immaculata.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Phylum Nematoda. A non-exhaustive list ofparticular genera includes, but is not limited to, Aphelenchoides spp.,Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp.,Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchusspp., and Radopholus spp. A non-exhaustive list of particular sp.includes, but is not limited to, Dirofilaria immitis, Heterodera zeae,Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus,Radopholus similis, and Rotylenchulus reniformis.

For additional information consult “HANDBOOK OF PEST CONTROL—THEBEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSEHOLD PESTS” by ArnoldMallis, 9th Edition, copyright 2004 by GIE Media Inc.

Applications

Controlling pests of Phyla Nematoda, Arthropoda, and/or Molluscagenerally means that pest populations, pest activity, or both, arereduced in an locus. This can come about when:

(a) pest populations are repulsed from a locus;

(b) pests are incapacitated in, or around, a locus; or

(c) pests are exterminated in, or around, a locus.

Of course, a combination of these results can occur. Generally, pestpopulations, activity, or both are desirably reduced more than fiftypercent, preferably more than 90 percent, and most preferably more than98 percent. Generally, the locus is not in, or on, a human;consequently, the locus is generally a non-human locus.

In another embodiment, the locus to which a molecule of Formula One isapplied can be any locus that is inhabited, or that may becomeinhabited, or that may be traversed, by a pest of Phyla Nematoda,Arthropoda, and/or Mollusca. For example, the locus can be:

(a) where crops, trees, fruits, cereals, fodder species, vines, turf,and/or ornamental plants, are growing;

(b) where domesticated animals are residing;

(c) the interior or exterior surfaces of buildings (such as places wheregrains are stored);

(d) the materials of construction used in buildings (such as impregnatedwood); and

(e) the soil around buildings.

Particular crop areas to use a molecule of Formula One include areaswhere apples, corn, sunflowers, cotton, soybeans, canola, wheat, rice,sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce,strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds,sugar beets, beans and other valuable crops are growing or the seedsthereof are going to be planted. It is also advantageous to use ammoniumsulfate with a molecule of Formula One when growing various plants.

In another embodiment, molecules of Formula One are generally used inamounts from about 0.0001 grams per hectare to about 5000 grams perhectare to provide control. In another embodiment, it is preferred thatmolecules of Formula One are used in amounts from about 0.001 grams perhectare to about 500 grams per hectare. In another embodiment, it ismore preferred that molecules of Formula One are used in amounts fromabout 0.01 gram per hectare to about 50 grams per hectare.

The molecules of Formula One may be used in mixtures, appliedsimultaneously or sequentially, alone or with other compounds to enhanceplant vigor (e.g. to grow a better root system, to better withstandstressful growing conditions). Such other compounds are, for example,compounds that modulate plant ethylene receptors, most notably1-methylcyclopropene (also known as 1-MCP). Furthermore, such moleculesmay be used during times when pest activity is low, such as before theplants that are growing begin to produce valuable agriculturalcommodities. Such times include the early planting season when pestpressure is usually low.

The molecules of Formula One can be applied to the foliar and fruitingportions of plants to control pests. The molecules will either come indirect contact with the pest, or the pest will consume the pesticidewhen eating leaf, fruit mass, or extracting sap, that contains thepesticide. The molecules of Formula One can also be applied to the soil,and when applied in this manner, root and stem feeding pests can becontrolled. The roots can absorb a molecule taking it up into the foliarportions of the plant to control above ground chewing and sap feedingpests.

Generally, with baits, the baits are placed in the ground where, forexample, termites can come into contact with, and/or be attracted to,the bait. Baits can also be applied to a surface of a building,(horizontal, vertical, or slant surface) where, for example, ants,termites, cockroaches, and flies, can come into contact with, and/or beattracted to, the bait. Baits can comprise a molecule of Formula One.

The molecules of Formula One can be encapsulated inside, or placed onthe surface of a capsule. The size of the capsules can range fromnanometer size (about 100-900 nanometers in diameter) to micrometer size(about 10-900 microns in diameter).

Because of the unique ability of the eggs of some pests to resistcertain pesticides, repeated applications of the molecules of FormulaOne may be desirable to control newly emerged larvae.

Systemic movement of pesticides in plants may be utilized to controlpests on one portion of the plant by applying (for example by sprayingan area) the molecules of Formula One to a different portion of theplant. For example, control of foliar-feeding insects can be achieved bydrip irrigation or furrow application, by treating the soil with forexample pre- or post-planting soil drench, or by treating the seeds of aplant before planting.

Seed treatment can be applied to all types of seeds, including thosefrom which plants genetically modified to express specialized traitswill germinate. Representative examples include those expressingproteins toxic to invertebrate pests, such as Bacillus thuringiensis orother insecticidal toxins, those expressing herbicide resistance, suchas “Roundup Ready” seed, or those with “stacked” foreign genesexpressing insecticidal toxins, herbicide resistance,nutrition-enhancement, drought resistance, or any other beneficialtraits. Furthermore, such seed treatments with the molecules of FormulaOne may further enhance the ability of a plant to better withstandstressful growing conditions. This results in a healthier, more vigorousplant, which can lead to higher yields at harvest time. Generally, about1 gram of the molecules of Formula One to about 500 grams per 100,000seeds is expected to provide good benefits, amounts from about 10 gramsto about 100 grams per 100,000 seeds is expected to provide betterbenefits, and amounts from about 25 grams to about 75 grams per 100,000seeds is expected to provide even better benefits.

It should be readily apparent that the molecules of Formula One may beused on, in, or around plants genetically modified to expressspecialized traits, such as Bacillus thuringiensis or other insecticidaltoxins, or those expressing herbicide resistance, or those with“stacked” foreign genes expressing insecticidal toxins, herbicideresistance, nutrition-enhancement, or any other beneficial traits.

The molecules of Formula One may be used for controlling endoparasitesand ectoparasites in the veterinary medicine sector or in the field ofnon-human animal keeping. The molecules of Formula One are applied, suchas by oral administration in the form of, for example, tablets,capsules, drinks, granules, by dermal application in the form of, forexample, dipping, spraying, pouring on, spotting on, and dusting, and byparenteral administration in the form of, for example, an injection.

The molecules of Formula One may also be employed advantageously inlivestock keeping, for example, cattle, sheep, pigs, chickens, andgeese. They may also be employed advantageously in pets such as, horses,dogs, and cats. Particular pests to control would be fleas and ticksthat are bothersome to such animals. Suitable formulations areadministered orally to the animals with the drinking water or feed. Thedosages and formulations that are suitable depend on the species.

The molecules of Formula One may also be used for controlling parasiticworms, especially of the intestine, in the animals listed above.

The molecules of Formula One may also be employed in therapeutic methodsfor human health care. Such methods include, but are limited to, oraladministration in the form of, for example, tablets, capsules, drinks,granules, and by dermal application.

Pests around the world have been migrating to new environments (for suchpest) and thereafter becoming a new invasive species in such newenvironment. The molecules of Formula One may also be used on such newinvasive species to control them in such new environment.

The molecules of Formula One may also be used in an area where plants,such as crops, are growing (e.g. pre-planting, planting, pre-harvesting)and where there are low levels (even no actual presence) of pests thatcan commercially damage such plants. The use of such molecules in sucharea is to benefit the plants being grown in the area. Such benefits,may include, but are not limited to, improving the health of a plant,improving the yield of a plant (e.g. increased biomass and/or increasedcontent of valuable ingredients), improving the vigor of a plant (e.g.improved plant growth and/or greener leaves), improving the quality of aplant (e.g. improved content or composition of certain ingredients), andimproving the tolerance to abiotic and/or biotic stress of the plant.

Before a pesticide can be used or sold commercially, such pesticideundergoes lengthy evaluation processes by various governmentalauthorities (local, regional, state, national, and international).Voluminous data requirements are specified by regulatory authorities andmust be addressed through data generation and submission by the productregistrant or by a third party on the product registrant's behalf, oftenusing a computer with a connection to the World Wide Web. Thesegovernmental authorities then review such data and if a determination ofsafety is concluded, provide the potential user or seller with productregistration approval. Thereafter, in that locality where the productregistration is granted and supported, such user or seller may use orsell such pesticide.

A molecule according to Formula One can be tested to determine itsefficacy against pests. Furthermore, mode of action studies can beconducted to determine if said molecule has a different mode of actionthan other pesticides. Thereafter, such acquired data can bedisseminated, such as by the internet, to third parties.

The headings in this document are for convenience only and must not beused to interpret any portion hereof.

Table Section

TABLE 1 Structures for Intermediates No. Preparation Structure C13 Ex 9

C1b Ex 1

C14 Ex 10

C8 Ex 4

C6 Ex 4

C7 Ex 4

C15a Ex 10a

C16 Ex 11

C15 Ex 10

C4 Ex 3

C3 Ex 3

C5 Ex 3

C53 Ex 56

C52 Ex 56

C24 Ex 24

C19 Ex 14

C20 Ex 15

C40 Ex 43

C41 Ex 44

C37 Ex 37

C30 Ex 30

C32 Ex 31

C31 Ex 30

C33 Ex 31

C34a Ex 32a

C38 Ex 38

C39 Ex 39

C17 Ex 13

C18 Ex 13

C22 Ex 20

C36 Ex 36

C26 Ex 26

C27 Ex 26

C28 Ex 27

C50 Ex 54

C55 Ex 58

C43 Ex 47

C44 Ex 48

C46 Ex 50

C47 Ex 51

C45 Ex 49

C58 Ex 60

C59 Ex 61

C60 Ex 62

C61 Ex 65

TABLE 1A Structures for Intermediates (CA) No. Preparation Structure CA1Ex 10

CA2 Ex 10

CA3 Ex 11

CA4 Ex 13

CA5 Ex 13

CA6 Ex 24

CA7 Ex 25

CA8 Ex 30

CA9 Ex 30

CA10 Ex 31

CA11 Ex 31

CA12 Ex 44

CA13 Ex 51

CA14 Ex 59

CA15 Ex 59

CA16 Ex 59

CA17 Ex 59

CA18 Ex 62

CA19 Ex 62

CA20 Ex 62

CA21 Ex 62

CA22 Ex 62

CA23 Ex 65

CA24 Ex 66

CA25 Ex 66

CA26 Ex 66

CA33 Ex 68

CA35 Ex 68

CA36 Ex 68

CA37 Ex 68

CA38 Ex 69

CA40 Ex 69

CA41 Ex 69

CA42 Ex 69

CA44 Ex 74

CA45 Ex 76

CA48 Ex 81

CA49 Ex 83

CA50 Ex 84

CA51 Ex 58

TABLE 1B Structures for Intermediates (PC) No. Preparation StructurePC1  Ex 71

PC2  Ex 71

PC3  Ex 71

PC5  Ex 71

PC6  Ex 71

PC7  Ex 71

PC8  Ex 71

PC14  Ex 71

PC15  Ex 71

PC16  Ex 71

PC74  Ex 75

PC75  Ex 75

PC76  Ex 75

PC80  Ex 75

PC81  Ex 75

PC83  Ex 75

PC84  Ex 75

PC85  Ex 75

PC87  Ex 75

PC92  Ex 63

PC93  Ex 63

PC94  Ex 63

PC99  Ex 63

PC101 Ex 63

PC102 Ex 63

PC103 Ex 63

PC105 Ex 63

PC118 Ex 63

PC119 Ex 63

PC120 Ex 63

PC124 Ex 63

PC125 Ex 63

PC127 Ex 63

PC128 Ex 63

PC129 Ex 63

PC131 Ex 63

PC144 Ex 63

PC145 Ex 63

PC146 Ex 63

PC150 Ex 63

PC151 Ex 63

PC152 Ex 63

PC153 Ex 63

PC154 Ex 63

PC155 Ex 63

PC156 Ex 63

PC159 Ex 63

PC160 Ex 63

PC170 Ex 63

PC171 Ex 63

PC172 Ex 63

PC176 Ex 63

PC179 Ex 63

PC180 Ex 63

PC181 Ex 63

PC182 Ex 63

TABLE 1C Structures for Intermediates (CB) No. Preparation StructureCB2  Ex 8 

CB3  Ex 8 

CB7  Ex 9 

CB8  Ex 9 

CB9  Ex 9 

CB10 Ex 10 

CB11 Ex 10 

CB12 Ex 13 

CB13 Ex 13 

CB14 Ex 13 

CB15 Ex 30 

CB16 Ex 30 

CB17 Ex 30 

CB18 Ex 31 

CB19 Ex 31 

CB23 Ex 51 

CB24 Ex 58 

CB25 Ex 58 

CB26 Ex 58 

CB27 Ex 58 

CB28 Ex 66 

CB29 Ex 66 

CB30 Ex 66 

CB31 Ex 68 

CB32 Ex 69 

CB33 Ex 70 

CB34 Ex 74 

CB35 Ex 86 

CB36 Ex 86 

CB37 Ex 87 

CB38 Ex 87 

CB39 Ex 87 

CB40 Ex 87 

CB41 Ex 87 

CB42 Ex 88 

CB43 Ex 88 

CB44 Ex 88 

CB45 Ex 88 

CB46 Ex 88 

CB47 Ex 89 

CB48 Ex 89 

CB49 Ex 89 

CB50 Ex 89 

CB51 Ex 89 

CB53 Ex 91 

CB54 Ex 92 

CB55 Ex 93 

CB56 Ex 94 

CB57 Ex 97 

CB58 Ex 98 

CB59 Ex 99 

CB60 Ex 99 

CB61 Ex 100

CB62 Ex 100

CB63 Ex 102

CB64 Ex 102

CB65 Ex 102

CB66 Ex 102

CB67 Ex 103

CB68 Ex 103

CB69 Ex 103

TABLE 2A Structures for Molecules of Formula One No. Structure F1 

F2 

F3 

F4 

F5 

 F5A

F6 

F7 

F8 

F9 

F10

F11

F12

F13

F14

F15

F16

F17

F18

F19

F20

F21

F22

F23

F24

F25

F26

F27

F28

F29

F30

F31

F32

F33

F34

F35

TABLE 2B Exemplified Prophetic Structures (P) from Table P-One and P-Twofor Molecules of Formula One No. Structure P1  

P2,   P532 

P3,   P1172

P5  

P6  

P7  

P8,   P852 

P14 

P15 

P20 

P26 

P27 

P28 

P29 

P30 

P31 

P33 

P42 

P44 

P45 

P47 

P49 

P50 

P51 

P52 

P53 

P57 

P58 

P59 

P64 

P65 

P66,   P353 

P74 

P75 

P76 

P80 

P81 

P83 

P84 

P85 

P87 

P92 

P93,   P510 

P94,   P197 

P99,   P830 

P101 

P102 

P103,  P1150

P105 

P118 

P119 

P120 

P124 

P125 

P127 

P128 

P129 

P131 

P144 

P145,  P522 

P146,  P208 

P150,  P363 

P151,  P842 

P152,  P1481

P153 

P154 

P155,  P1162

P156,  P682 

P159 

P160 

P170 

P171 

P172 

P176 

P179 

P180 

P181 

P182 

P205 

P209 

P364 

P679 

P683 

P1163

TABLE 2C Additionally Exemplified Molecules (FB) of Formula One No.Structure FB1 

FB2 

FB3 

FB4 

FB5 

FB6 

FB7 

FB8 

FB9 

FB10

FB11

FB12

FB13

FB14

FB15

FB16

FB17

FB18

FB19

FB20

FB21

FB22

FB23

FB24

FB25

FB26

FB27

FB28

FB29

FB30

FB31

FB32

FB33

FB34

FB35

FB36

FB37

FB38

FB39

FB40

FB41

FB42

FB43

FB44

FB45

FB46

FB47

FB48

FB49

FB50

FB51

FB52

FB53

FB54

FB55

FB56

FB57

FB58

FB59

FB60

FB61

FB62

FB63

FB64

FB65

FB66

FB67

FB68

FB69

FB70

FB71

FB72

TABLE 3a Analytical Data for Compounds in Table 2a. ¹³C NMR or No.Appearance Mp (° C.) ESIMS m/z ¹H NMR (δ)^(a) ¹⁹F NMR (δ) F1 Clear 609([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 oil CDCl₃) δ 8.55 (s, MHz,CDCl₃) 1H), 8.08 (d, J = δ −58.02 8.2 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H),7.43 (dd, J = 3.4, 2.1 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.31-7.24 (m,3H), 7.03 (d, J = 7.6 Hz, 1H), 5.51 (t, J = 6.1 Hz, 1H), 3.93 (d, J =1.4 Hz, 2H), 3.63- 3.39 (m, 2H), 2.86 (t, J = 7.0 Hz, 2H), 2.68 (dt, J =13.7, 6.9 Hz, 1H), 1.17 (dd, J = 6.8, 4.7 Hz, 6H) F2 White 150-153 569([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 powder CDCl₃) δ 10.12 (s, MHz,CDCl₃) 1H), 9.40 (s, 1H), δ −52.21 8.08 (dt, J = 4.3, 2.7 Hz, 3H), 7.63(d, J = 8.3 Hz, 2H), 7.46-7.14 (m, 6H), 7.00 (s, 1H), 3.52- 3.39 (m,2H), 2.98 (dd, J = 13.7, 6.8 Hz, 1H), 2.86 (t, J = 6.9 Hz, 2H), 1.15 (d,J = 6.8 Hz, 6H) F3 White 133-136, 582 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹FNMR (376 solid 148-149 CDCl₃) δ 11.82 (s, MHz, CDCl₃) 1H), 9.75 (s, 1H),δ −58.02 8.56 (s, 1H), 8.17- 8.08 (m, 2H), 7.84- 7.74 (m, 2H), 7.38 (dq,J = 8.0, 0.9 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.26- 7.07 (m, 3H), 5.75(s, 1H), 3.52 (d, J = 7.2 Hz, 2H), 3.12- 2.97 (m, 1H), 2.90 (d, J = 7.5Hz, 2H), 2.33 (s, 3H), 1.22 (d, J = 6.8 Hz, 6H) F4 White 88° C. 583([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 solid (dec) CDCl₃) δ 11.90 (s,MHz, CDCl₃) 1H), 9.96 (s, 1H), δ −58.03 8.55 (s, 1H), 8.12 (d, J = 8.2Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H), 7.42-7.33 (m, 5H), 7.30 (d, J = 8.2Hz, 2H), 7.23 (dd, J = 12.0, 5.8 Hz, 1H), 5.81 (s, 1H), 4.19-4.13 (m,1H), 3.13 (ddd, J = 27.5, 13.7, 6.9 Hz, 1H), 2.94 (dd, J = 13.4, 6.0 Hz,1H), 2.74 (dd, J = 13.3, 7.6 Hz, 1H), 1.32- 1.16 (m, 9H) F5 Pale 102° C.623 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 pink (dec) CDCl₃) δ 8.55(s, MHz, CDCl₃) solid 1H), 8.11-8.05 (m, δ −58.02 2H), 7.84-7.76 (m,2H), 7.44-7.36 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.27- 7.25 (m, 3H),6.85 (d, J = 0.8 Hz, 1H), 5.51 (t, J = 6.1 Hz, 1H), 3.92 (d, J = 1.7 Hz,2H), 3.68- 3.38 (m, 2H), 2.87 (t, J = 7.1 Hz, 2H), 2.73-2.52 (m, 1H),2.33 (s, 3H), 1.15 (dd, J = 6.9, 2.4 Hz, 6H) F5A 60-70 ¹H NMR (400 MHz,DMSO-d₆) δ 9.39 (s, 1H), 8.13-8.03 (m, 2H), 8.03- 7.96 (m, 2H), 7.69-7.57 (m, 3H), 7.50 (d, J = 7.8 Hz, 2H), 7.39-7.27 (m, 3H), 7.22 (dd, J =8.0, 1.9 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 6.98 (dd, J = 1.7, 0.9 Hz,1H), 4.11 (d, J = 17.9 Hz, 1H), 4.00 (d, J = 17.9 Hz, 1H), 3.27 (q, J =6.8 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 2.61 (p, J = 6.8 Hz, 1H), 2.30(s, 3H), 2.28 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.09- 1.04 (m, 3H)(SO₃H not observed) F6 Orange 110-118° C. 639 ([M + H]⁺) ¹H NMR (400MHz, ¹⁹F NMR (376 solid CDCl₃) δ 8.56 (d, MHz, CDCl₃) J = 3.6 Hz, 1H),8.12- δ −58.02 8.05 (m, 2H), 7.84- 7.76 (m, 2H), 7.39 (d, J = 8.3 Hz,2H), 7.32 (d, J = 8.8 Hz, 1H), 7.29-7.25 (m, 2H), 6.99 (dd, J = 8.7, 2.7Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 5.52 (t, J = 5.9 Hz, 1H), 3.93 (d, J= 1.6 Hz, 2H), 3.77 s, 3H), 3.67-3.38 (m, 2H), 2.87 (t, J = 7.1 Hz, 2H),2.60 (dt, J = 13.7, 6.9 Hz, 1H), 1.20 (dt, J = 13.0, 6.8 Hz, 6H) F7White 114° C. 623 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 solid (dec)CDCl₃) δ 8.55 (d, MHz, CDCl₃) J = 1.0 Hz, 1H), 8.12- δ −58.02 8.03 (m,2H), 7.85- 7.75 (m, 2H), 7.50- 7.43 (m, 2H), 7.43- 7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.29- 7.22 (m, 2H), 7.09- 7.01 (m, 1H), 5.35 (dd, J =15.3, 8.4 Hz, 1H), 4.14 (dd, J = 14.6, 7.5 Hz, 1H), 3.92 (t, J = 1.8 Hz,2H), 2.93 (ddd, J = 46.3, 13.4, 5.6 Hz, 1H), 2.83-2.59 (m, 2H), 1.17(ddd, J = 6.6, 3.7, 2.7 Hz, 6H), 1.14-1.03 (m, 3H) F8 Off- 114° C. 637([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 white (dec) CDCl₃) δ 8.56 (s,MHz, CDCl₃) solid 1H), 8.12-8.02 (m, δ −58.03 2H), 7.84-7.74 (m, 2H),7.39 (d, J = 8.6 Hz, 2H), 7.36- 7.31 (m, 1H), 7.28 (d, J = 7.4 Hz, 2H),7.24 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 12.4 Hz, 1H), 5.36 (dd, J = 14.8,8.4 Hz, 1H), 3.95-3.87 (m, 2H), 3.00 (dd, J = 13.6, 5.5 Hz, 1H), 2.87(dd, J = 13.4, 5.6 Hz, 1H), 2.76 (dd, J = 13.4, 7.1 Hz, 1H), 2.71-2.57(m, 1H), 2.35 (d, J = 7.9 Hz, 3H), 1.19- 1.05 (m, 9H) F9 Brown 673 ([M +H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 gum CDCl₃) δ 8.56 (s, MHz, CDCl₃)1H), 8.08 (d, J = δ −85.89, −87.85 8.1 Hz, 2H), 7.85- 7.77 (m, 2H),7.43- 7.37 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.28-7.22 (m, 3H),6.86-6.83 (m, 1H), 5.52 (t, J = 6.2 Hz, 1H), 3.92 (d, J = 1.7 Hz, 2H),3.52 (ddt, J = 35.7, 13.7, 6.7 Hz, 2H), 2.87 (t, J = 7.1 Hz, 2H), 2.63(p, J = 7.0 Hz, 1H), 2.33 (s, 3H), 1.15 (dd, J = 6.9, 2.2 Hz, 6H) F10Orange 113° C. 637 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 solid (dec)CDCl₃) δ 8.55 (s, MHz, CDCl₃) 1H), 8.08 (dd, J = δ −58.03 8.1, 5.9 Hz,2H), 7.84-7.76 (m, 2H), 7.39 (dddd, J = 7.9, 3.0, 2.1, 1.2 Hz, 2H),7.31-7.20 (m, 4H), 6.83 (ddd, J = 6.6, 1.8, 0.9 Hz, 1H), 5.42 (t, J =4.0 Hz, 1H), 3.90 (s, 2H), 3.66-3.18 (m, 2H), 3.02 (p, J = 7.2 Hz, 1H),2.60 (dq, J = 14.1, 7.0 Hz, 1H), 2.34-2.26 (m, 3H), 1.27 (d, J = 7.2 Hz,3H), 1.17- 1.07 (m, 6H) F11 Yellow 178-182° C. 567 ([M + H]⁺) ¹H NMR(400 MHz, ¹⁹F NMR (376 solid DMSO-d₆) δ 11.74 MHz, DMSO-d₆) (s, 1H),10.27 (s, δ −56.96 1H), 9.40 (s, 2H), 8.18-7.91 (m, 4H), 7.59 (dd, J =24.9, 8.4 Hz, 4H), 7.41 (ddd, J = 9.4, 7.9, 4.1 Hz, 3H), 7.27 (dtd, J =25.3, 7.4, 1.5 Hz, 2H), 6.25 (d, J = 14.6 Hz, 1H), 3.04 (dt, J = 13.7,6.8 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H) F12 Orange 128° C. 607 ([M + H]⁺)¹H NMR (400 MHz, ¹⁹F NMR (376 solid (dec) CDCl₃) δ 8.54 (s, MHz, CDCl₃)1H), 8.09 (d, J = δ −58.02 8.4 Hz, 2H), 7.81- 7.76 (m, 2H), 7.52- 7.47(m, 2H), 7.48- 7.41 (m, 1H), 7.41- 7.35 (m, 5H), 7.34 (s, 1H), 7.10-7.05(m, 1H), 6.03 (d, J = 14.6 Hz, 1H), 3.98 (d, J = 2.4 Hz, 2H), 2.69 (dt,J = 13.7, 6.8 Hz, 1H), 1.22-1.18 (m, 6H) F13 Orange 621 ([M + H]⁺) ¹HNMR (400 MHz, ¹⁹F NMR (376 gum CDCl₃) δ 8.56 (d, J = MHz, CDCl₃) 1.4 Hz,1H), 8.16 δ −58.02 8.06 (m, 2H), 7.87- 7.74 (m, 2H), 7.53- 7.45 (m, 3H),7.42- 7.30 (m, 3H), 7.26- 7.21 (m, 2H), 7.14- 7.01 (m, 2H), 3.98 (d, J =2.2 Hz, 2H), 2.77-2.60 (m, 1H), 1.98 (d, J = 1.3 Hz, 3H), 1.21 (dd, J =6.9, 5.1 Hz, 6H) F14 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376Solid 555 ([M + H]⁺), DMSO-d₆) δ 11.95 MHz, DMSO-d₆) 553 ([M − H]⁻) (s,1H), 10.26 (s, δ −56.96. 1H), 9.43 (s, 1H), 8.21-8.06 (m, 4H), 7.65(ddd, J = 7.9, 2.0, 1.0 Hz, 2H), 7.55 (t, J = 5.9 Hz, 1H), 7.53-7.47 (m,2H), 7.44 (dd, J = 7.7, 1.5 Hz, 1H), 7.38 (dd, J = 7.7, 1.6 Hz, 1H),7.30 (td, J = 7.5, 1.6 Hz, 1H), 7.23 (td, J = 7.5, 1.7 Hz, 1H), 4.46 (d,J = 5.8 Hz, 2H), 3.04 (hept, J = 6.8 Hz, 1H), 1.20 (d, J = 6.8 Hz, 6H).F15 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 605 ([M + H]⁺),DMSO-d₆) δ 11.93 MHz, DMSO-d₆) 603 ([M − H]⁻) (s, 1H), 10.25 (s, δ−85.19, −86.91. 1H), 9.42 (s, 1H), 8.33-8.02 (m, 4H), 7.68-7.56 (m, 2H),7.60-7.05 (m, 7H), 4.45 (d, J = 5.8 Hz, 2H), 3.02 (hept, J = 7.1 Hz,1H), 1.18 (d, J = 6.8 Hz, 6H). F16 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹FNMR (376 Solid 619 ([M + H]⁺), DMSO-d₆) δ 11.89 MHz, DMSO-d₆) 617 [M −H)⁻] (s, 1H), 10.25 (s, δ −85.19, −86.91. 1H), 9.44 (s, 1H), 8.17-8.08(m, 4H), 7.73-7.61 (m, 2H), 7.60-7.40 (m, 3H), 7.33-7.18 (m, 2H),7.17-7.05 (m, 1H), 4.46 (d, J = 5.8 Hz, 2H), 2.99 (hept, J = 6.6 Hz,1H), 2.29 (s, 3H), 1.17 (d, J = 6.8 Hz, 6H). F17 White ESIMS m/z ¹H NMR(400 MHz, ¹⁹F NMR (376 Solid 595 ([M + H]⁺), DMSO-d₆) δ 9.41 MHz,DMSO-d₆) 593 ([M − H]⁻) (d, J = 3.4 Hz, 1H), δ −56.96. 8.18 (t, J = 6.3Hz, 1H), 8.11-8.02 (m, 4H), 7.68-7.61 (m, 2H), 7.53-7.42 (m, 2H),7.40-7.27 (m, 3H), 7.23 (dd, J = 7.9, 1.4 Hz, 1H), 4.37-4.00 (m, 4H),2.71 (p, J = 6.8 Hz, 1H), 1.16 (dd, J = 27.4, 6.8 Hz, 6H). F18 Off ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR (376 White 645 ([M + H]⁺), DMSO-d₆) δ 9.40MHz, DMSO-d₆) Solid 643 ([M − H]⁻) (d, J = 3.0 Hz, 1H), δ −85.19,−86.92. 8.16 (t, J = 6.3 Hz, 1H), 8.13-7.99 (m, 4H), 7.69-7.58 (m, 2H),7.58-7.39 (m, 2H), 7.40-7.06 (m, 4H), 4.40-3.94 (m, 4H), 2.70 (p, J =6.8 Hz, 1H), 1.22- 1.08 (m, 6H). F19 White ESIMS m/z ¹H NMR (400 MHz,¹⁹F NMR (376 Solid 659 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz, DMSO-d₆) 657 ([M− H]⁻) (s, 1H), 8.18 (t, J = δ −85.21 6.3 Hz, 1H), 8.15- (d, J = 9.47.98 (m, 4H), 7.68- Hz), −86.93 (d, 7.57 (m, 2H), 7.51- J = 7.3 Hz).7.19 (m, 4H), 7.05- 6.96 (m, 1H), 4.42- 3.92 (m, 4H), 2.64 (p, J = 6.9Hz, 1H), 2.29 (s, 3H), 1.28- 0.96 (m, 6H). F20 White 124-128 ESIMS m/z¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 637 ([M + H]⁺) CDCl₃) δ 8.55 (s,MHz, CDCl₃) 1H), 8.11-8.05 (m, δ −58.03. 2H), 7.83-7.76 (m, 2H),7.42-7.35 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.26 (s, 3H), 6.87-6.83 (m,1H), 5.48 (t, J = 6.1 Hz, 1H), 3.98- 3.84 (m, 2H), 3.37- 3.18 (m, 2H),2.74- 2.57 (m, 3H), 2.35 (s, 3H), 1.86 (dt, J = 14.8, 7.3 Hz, 2H), 1.16(dd, J = 6.9, 2.7 Hz, 6H). F21 White 97 ESIMS m/z ¹H NMR (400 MHz, ¹⁹FNMR (376 Solid (dec.) 597 ([M + H]⁺) DMSO-d₆) δ 11.91 MHz, DMSO-d₆) (s,1H), 10.05 (s, δ −56.96. 1H), 9.39 (s, 1H), 8.11-8.01 (m, 4H), 7.67-7.56(m, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.08 (d, J= 8.0 Hz, 2H), 3.16 (q, J = 6.5 Hz, 2H), 2.95 (p, J = 6.9 Hz, 1H), 2.74-2.66 (m, 2H), 2.26 (s, 3H), 1.88-1.76 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H).F22 White 197-198° C. 581 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 solidDMSO-d₆) δ 11.87 MHz, DMSO-d₆) (s, 1H), 10.02 (s, δ −57.00 1H), 9.38 (s,1H), 8.09-8.04 (m, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.3 Hz,2H), 7.41- 7.18 (m, 7H), 2.99 (dd, J = 13.7, 6.8 Hz, 1H), 2.90 (s, 1H),2.16 (s, 1H), 1.36-1.22 (m, 3H), 1.17 (d, J = 7.3 Hz, 6H) F23 Off-185-190° C. 581 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 white DMSO-d₆)δ 11.98 MHz, DMSO-d₆) solid (s, 1H), 10.01 (s, δ −56.97 1H), 9.38 (s,1H), 8.11-8.03 (m, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.67-7.52 (m, 3H),7.39 (s, 1H), 7.35-7.15 (m, 5H), 2.88 (s, 1H), 2.53- 2.50 (m, 2H), 2.15(d, J = 6.4 Hz, 1H), 1.59-1.45 (m, 2H), 1.39-1.21 (m, 2H), 0.88 (t, J =7.3 Hz, 3H) F24 White 127° C. 581 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR(376 solid (dec) DMSO-d₆) δ 11.51 MHz, DMSO-d₆) (s, 1H), 10.01 (s, δ−56.97 1H), 9.38 (s, 1H), 8.10-8.03 (m, 2H), 8.01 (d, J = 8.1 Hz, 2H),7.61 (d, J = 8.5 Hz, 2H), 7.36 (s, 1H), 7.29 (dd, J = 8.3, 1.3 Hz, 2H),7.22-7.02 (m, 3H), 2.90 (d, J = 3.3 Hz, 1H), 2.53-2.45 (m, 2H), 2.17 (d,J = 6.1 Hz, 4H), 1.35- 1.18 (m, 2H), 1.12 (q, J = 7.5 Hz, 3H) F25 White127° C. 567 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 solid (dec)DMSO-d₆) δ 11.46 MHz, DMSO-d₆) (s, 1H), 10.00 (s, δ −56.97 1H), 9.38 (s,1H), 8.11-8.04 (m, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.3 Hz,2H), 7.35 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.16- 7.03 (m, 3H), 2.89(d, J = 3.1 Hz, 1H), 2.51 (s, 1H), 2.16 (d, J = 7.2 Hz, 6H), 1.34-1.23(m, 2H) F26 White 583 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 oilyDMSO-d₆) δ 11.70 MHz, DMSO-d₆) solid (s, 1H), 9.95 (s, δ −56.98 1H),9.38 (s, 1H), 8.11-8.05 (m, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.62 (d, J =8.3 Hz, 2H), 7.32 (dd, J = 23.5, 8.5 Hz, 4H), 6.91-6.69 (m, 2H), 3.74(s, 3H), 2.87 (s, 1H), 2.16 (s, 4H), 1.34- 1.18 (m, 2H) F27 Off-111-121° C. 581 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 white CDCl₃) δ11.92 (s, MHz, CDCl₃) solid 1H), 10.23 (s, 1H), δ −58.02 8.60 (s, 1H),8.13- 8.01 (m, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.7 Hz, 3H),7.26 (s, 1H), 7.19 (d, J = 7.9 Hz, 3H), 7.11 (d, J = 7.6 Hz, 1H), 2.86(s, 1H), 2.69-2.53 (m, 2H), 2.34 (s, 4H), 1.21 (t, J = 7.6 Hz, 5H) F28White 181-184° C. 595 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 solidCDCl₃) δ 11.70 (d, MHz, CDCl₃) J = 130.0 Hz, 1H), δ −58.03 10.03 (d, J =115.9 Hz, 1H), 8.58 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 9.0Hz, 2H), 7.38 (d, J = 8.4 Hz, 3H), 7.27-7.25 (m, 1H), 7.18 (dd, J =21.1, 8.0 Hz, 4H), 3.07 (dt, J = 13.9, 6.8 Hz, 1H), 2.87 (s, 1H), 2.34(s, 3H), 2.18 (s, 1H), 1.28-1.19 (m, 8H) F29 Off- 116° C. 621 ([M + H]⁺)¹H NMR (400 MHz, ¹⁹F NMR (376 white (dec) CDCl₃) δ 8.54 (s, MHz, CDCl₃)solid 1H), 8.07 (d, J = δ −58.04 8.3 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H),7.48-7.43 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.35-7.28 (m, 1H),7.23-7.17 (m, 2H), 7.05 (dd, J = 7.5, 2.7 Hz, 1H), 5.69 (dd, J = 7.1,2.9 Hz, 1H), 3.94 (d, J = 2.3 Hz, 2H), 2.98-2.90 (m, 1H), 2.74-2.63 (m,1H), 2.13-2.03 (m, 1H), 1.33-1.22 (m, 2H), 1.22-1.16 (m, 6H) F30 Off-621 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 white CDCl₃) δ 8.54 (s,MHz, CDCl₃) oily 1H), 8.08 (d, J = δ −58.04 solid 8.3 Hz, 2H), 7.79 (d,J = 9.0 Hz, 2H), 7.46-7.30 (m, 5H), 7.21 (dd, J = 8.3, 2.7 Hz, 2H), 7.07(d, J = 7.8 Hz, 1H), 5.69 (s, 1H), 3.93 (d, J = 2.6 Hz, 2H), 2.93 (s,1H), 2.40 (dd, J = 8.7, 6.9 Hz, 2H), 2.09 (d, J = 9.7 Hz, 1H), 1.64-1.56 (m, 2H), 1.36- 1.13 (m, 2H), 0.93 (td, J = 7.3, 1.8 Hz, 3H) F31Clear 621 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 oil CDCl₃) δ 8.54 (s,MHz, CDCl₃) 1H), 8.07 (d, J = δ −58.03 8.3 Hz, 2H), 7.79 (d, J = 9.0 Hz,2H), 7.41-7.29 (m, 3H), 7.20 (dd, J = 13.3, 7.9 Hz, 4H), 5.72 (s, 1H),3.95 (s, 2H), 2.94 (dd, J = 7.4, 4.1 Hz, 1H), 2.43 (q, J = 7.7 Hz, 2H),2.16-2.06 (m, 4H), 1.31-1.22 (m, 2H), 1.17 (td, J = 7.6, 2.4 Hz, 3H) F32Clear 607 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 oil CDCl₃) δ 8.54 (s,MHz, CDCl₃) 1H), 8.08 (d, J = δ −58.04 8.3 Hz, 2H), 7.82- 7.76 (m, 2H),7.38 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 17.5,7.9 Hz, 4H), 5.71 (s, 1H), 3.95 (s, 2H), 2.94 (td, J = 7.6, 3.3 Hz, 1H),2.13 (d, J = 1.3 Hz, 6H), 2.12-2.06 (m, 1H), 1.32-1.17 (m, 2H) F33Yellow 124° C. 621 ([M + H]⁺) ¹H NMR (400 MHz, ¹⁹F NMR (376 solid (dec)CDCl₃) δ 8.54 (s, MHz, CDCl₃) 1H), 8.08 (d, J = δ −58.03 8.3 Hz, 2H),7.79 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.9 Hz,1H), 7.25- 7.16 (m, 2H), 6.89 (s, 1H), 5.71 (s, 1H), 3.92 (d, J = 2.0Hz, 2H), 2.94 (dd, J = 7.2, 3.6 Hz, 1H), 2.47-2.38 (m, 2H), 2.36 (d, J =2.3 Hz, 3H), 2.10 (ddd, J = 9.6, 6.4, 3.4 Hz, 1H), 1.33- 1.19 (m, 2H),1.16 (td, J = 7.6, 2.7 Hz, 3H) F34 Yellow 621 ([M + H]⁺) ¹H NMR (400MHz, ¹⁹F NMR (376 oil CDCl₃) δ 8.53 (s, MHz, CDCl₃) 1H), 8.04 (d, J = δ−58.02 8.1 Hz, 2H), 7.78 (d, J = 8.9 Hz, 3H), 7.37 (d, J = 8.5 Hz, 4H),7.19 (dd, J = 12.6, 7.2 Hz, 2H), 6.91 (s, 1H), 5.42 (d, J = 11.2 Hz,1H), 3.95-3.82 (m, 1H), 3.76 (ddd, J = 10.3, 7.5, 5.5 Hz, 1H), 3.26 (dd,J = 15.0, 7.2 Hz, 2H), 2.96-2.81 (m, 2H), 2.37-2.30 (m, 3H), 2.05-1.96(m, 1H), 1.29-1.05 (m, 8H) F35 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR(376 solid 569 ([M + H]⁺), DMSO-d₆) δ 11.89 MHz, DMSO-d₆) 567 ([M − H]⁻)(s, 1H), 10.25 (s, δ −56.96 1H), 9.43 (s, 1H), 8.19-8.05 (m, 4H),7.72-7.60 (m, 2H), 7.59-7.46 (m, 3H), 7.29-7.21 (m, 2H), 7.11 (dd, J =8.2, 1.7 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 2.99 (p, J = 6.9 Hz, 1H),2.29 (s, 3H), 1.17 (d, J = 6.9 Hz, 6H) ^(a)All ¹H NMR data measured inCDCl₃ at 400 MHz unless otherwise noted

TABLE 3b Analytical Data for Compounds in Table 2b. ¹³C NMR or No.Appearance Mp (° C.) ESIMS m/z ¹H NMR (δ)^(a) ¹⁹F NMR (δ) P1 White ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR (376 solid 567 ([M + H]⁺), DMSO-d₆) δ 9.39MHz, DMSO-d₆) 565 ([M − H]⁻) (s, 1H), 8.17 (t, J = δ −56.97 6.3 Hz, 1H),8.11- 8.00 (m, 4H), 7.67- 7.58 (m, 2H), 7.40-7.28 (m, 5H), 7.28-7.23 (m,1H), 4.25 (qd, J = 15.4, 6.3 Hz, 2H), 4.17-3.98 (m, 2H), 2.10 (s, 3H)P2, White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 P532 solid 581 ([M +H]⁺), DMSO-d₆) δ 9.38 MHz, DMSO-d₆) 579 ([M − H]⁻) (s, 1H), 8.15 (t, J =δ −56.97 6.3 Hz, 1H), 8.07- 8.05 (m, 2H), 8.03 (d, J = 8.2 Hz, 2H),7.64-7.60 (m, 3H), 7.41-7.39 (m, 2H), 7.36- 7.33 (m, 2H), 7.23 (dt, J =7.9, 0.9 Hz, 1H), 4.30-4.18 (m, 2H), 4.17- 3.99 (m, 2H), 2.41 (q, J =7.6 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H) P3, Off- ESIMS m/z ¹H NMR (400MHz, ¹⁹F NMR (376 P1172 white 613 ([M + H]⁺), DMSO-d₆) δ 9.39 MHz,DMSO-d₆) solid 611 ([M − H]⁻) (s, 1H), 8.17 (t, J = δ −56.97 6.3 Hz,1H), 8.13- (d, J = 3.4 7.99 (m, 5H), 7.62 Hz), −112.07 (d, J = 8.6 Hz,2H), (d, J = 3.6 Hz) 7.40-7.27 (m, 3H), 7.16 (td, J = 8.4, 2.9 Hz, 1H),4.25 (dd, J = 10.6, 6.3 Hz, 2H), 4.19- 3.95 (m, 2H), 2.75- 2.61 (m, 1H),1.20-1.08 (m, 6H) P5 Off- ESIMS m/z 8.55 (s, 1H), 8.11 ¹⁹F NMR (376white 609 ([M + H]⁺), (d, J = 8.3 Hz, 2H), MHz, CDCl₃) solid 607 ([M −H]⁻) 7.79 (d, J = 9.0 Hz, δ −58.02 2H), 7.40-7.32 (m, 4H), 7.22 (d, J =2.0 Hz, 1H), 7.12- 7.08 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.83 (t, J =6.1 Hz, 1H), 4.47 (t, J = 6.5 Hz, 2H), 3.93 (d, J = 1.8 Hz, 2H), 2.65(p, J = 6.9 Hz, 1H), 2.38 (s, 3H), 1.17 (d, J = 6.8 Hz, 6H) P6 Off-ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 white 597 ([M + H]⁺), DMSO-d₆) δ9.39 MHz, CDCl₃) solid 595 ([M − H]⁻) (s, 1H), 8.17 (t, J = δ −56.96 6.3Hz, 1H), 8.13- 7.99 (m, 4H), 7.70- 7.56 (m, 2H), 7.41-7.31 (m, 2H), 7.15(d, J = 8.7 Hz, 1H), 6.93 (d, J = 2.8 Hz, 1H), 6.86 (dd, J = 8.7, 2.9Hz, 1H), 4.25 (qd, J = 15.4, 6.3 Hz, 2H), 4.16- 3.94 (m, 2H), 3.78 (s,3H), 2.05 (s, 3H). P7 Off ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 White595 ([M + H]⁺), DMSO-d₆) δ 9.39 MHz, CDCl₃) Solid 593 ([M − H]⁻) (s,1H), 8.19 (t, J = δ −52.22 6.3 Hz, 1H), 8.13- 7.95 (m, 4H), 7.63 (d, J =8.5 Hz, 2H), 7.38-7.17 (m, 4H), 7.04 (d, J = 1.9 Hz, 1H), 4.24 (dd, J =13.7, 6.3 Hz, 2H), 4.13 (d, J = 18.1 Hz, 1H), 4.07 (d, J = 17.9 Hz, 1H),3.39 (q, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.10-1.08 (m, 3H). P8, Off ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR (376 P852 White 609 ([M + H]⁺) DMSO-d₆) δ9.45 MHz, CDCl₃) Solid (s, 1H), 8.23 (t, J = δ −52.21 6.3 Hz, 1H), 8.18-8.05 (m, 4H), 7.68 (d, J = 8.7 Hz, 2H), 7.44-7.38 (m, 2H), 7.37-7.23 (m,2H), 7.10 (d, J = 1.8 Hz, 1H), 4.30 (t, J = 6.7 Hz, 2H), 4.23-4.02 (m,2H), 3.50-3.42 (m, 2H), 2.37 (s, 3H), 1.63-1.47 (m, 2H), 1.15 (t, J =7.0 Hz, 3H) P14 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 579([M + H]⁺), DMSO-d₆) δ 9.52 MHz, CDCl₃) 577 ([M − H]⁻) (s, 1H), 8.18(dd, J = δ −60.80 7.2, 4.5 Hz, 3H), 8.08-8.02 (m, 2H), 8.02-7.94 (m,2H), 7.58- 7.40 (m, 2H), 7.39- 7.27 (m, 3H), 7.21 (dd, J = 7.9, 1.4 Hz,1H), 4.32- 4.18 (m, 2H), 4.18- 3.98 (m, 2H), 2.70 (p, J = 6.8 Hz, 1H),1.20-1.08 (m, 6H) P15 Light ESMIS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376Yellow 593 ([M + H]⁺), DMSO-d₆) δ 9.52 MHz, CDCl₃) Solid 591 ([M − H]⁻)(s, 1H), 8.20 (d, J = δ −60.80 8.4 Hz, 2H), 8.15 (t, J = 6.3 Hz, 1H),8.11-8.04 (m, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.40- 7.33 (m, 2H), 7.33-7.27 (m, 1H), 7.15-7.03 (m, 2H), 4.34-4.20 (m, 2H), 4.18- 3.97 (m, 2H),2.66 (p, J = 6.8 Hz, 1H), 2.37 (s, 3H), 1.11 (dt, J = 7.0, 3.6 Hz, 6H)P20 Off ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 White 607 ([M + H]⁺)DMSO-d₆) δ 9.38 MHz, CDCl₃) Solid (s, 1H), 8.14-8.01 δ −56.96 (m, 4H),7.70 (s, 1H), 7.62 (dq, J = 7.7, 1.0 Hz, 2H), 7.45-7.35 (m, 2H),7.34-7.27 (m, 1H), 7.15 (t, J = 1.3 Hz, 2H), 6.66 (q, J = 0.9 Hz, 1H),4.47-4.28 (m, 2H), 2.73-2.62 (m, 1H), 2.39 (s, 3H), 2.10 (d, J = 1.1 Hz,3H), 1.10 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H) P26 Brown ESIMSm/z 8.55 (s, 1H), 8.08 ¹⁹F NMR (376 Oil 623 ([M + H]⁺) (d, J = 8.2 Hz,2H), MHz, CDCl₃) 7.83-7.75 (m, δ −58.03 2H), 7.44-7.35 (m, 2H), 7.28-7.25 (m, 2H), 7.23- 7.18 (m, 1H), 7.09 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H),6.91 (d, J = 8.0 Hz, 1H), 5.51 (t, J = 6.2 Hz, 1H), 3.91 (d, J = 1.5 Hz,2H), 3.52 (ddt, J = 30.1, 13.6, 6.7 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H),2.63 (p, J = 6.8 Hz, 1H), 2.38 (s, 3H), 1.16 (dd, J = 6.9, 4.5 Hz, 6H)P27 Yellow ESIMS m/z 8.55 (s, 1H), 8.11- ¹⁹F NMR (376 Oil 623 ([M + H]⁺)8.05 (m, 2H), MHz, CDCl₃) 7.84-7.72 (m, δ −58.03 2H), 7.43-7.35 (m, 2H),7.27- 7.25 (m, 1H), 7.25 (s, 1H), 7.24-7.14 (m, 2H), 6.84 (dd, J = 7.3,2.0 Hz, 1H), 5.51 (t, J = 6.1 Hz, 1H), 3.91 (d, J = 1.5 Hz, 2H), 3.52(dp, J = 25.1, 6.7 Hz, 2H), 2.95 (dq, J = 15.6, 7.6 Hz, 1H), 2.87 (td, J= 7.0, 2.1 Hz, 2H), 2.47 (s, 3H), 1.25 (d, J = 7.2 Hz, 6H) P28 BrownESIMS m/z 8.55 (s, 1H), 8.11- ¹⁹F NMR (376 Foamy 627 ([M + H]⁺) 8.05 (m,2H), MHz, CDCl₃) Solid 7.83-7.74 (m, δ −58.02, −110.68 2H), 7.39 (dd, J= 9.1, 1.0 Hz, 2H), 7.29-7.24 (m, 2H), 7.09 (dd, J = 9.9, 2.6 Hz, 1H),7.06-6.93 (m, 2H), 5.48 (t, J = 6.2 Hz, 1H), 3.92 (d, J = 1.7 Hz, 2H),3.53 (dp, J = 25.1, 6.7 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H), 2.64 (pd, J =6.9, 1.9 Hz, 1H), 1.15 (t, J = 6.9 Hz, 6H) P29 Pale ESIMS m/z 8.55 (s,1H), 8.12- ¹⁹F NMR (376 Pink 623 ([M + H]⁺) 8.04 (m, 2H), MHz, CDCl₃)Solid 7.83-7.75 (m, δ −58.03 2H), 7.43-7.35 (m, 2H), 7.30- 7.26 (m, 2H),7.25- 7.17 (m, 2H), 6.90-6.83 (m, 1H), 5.52 (t, J = 6.2 Hz, 1H), 3.91(d, J = 2.4 Hz, 2H), 3.62-3.43 (m, 2H), 2.88 (t, J = 7.1 Hz, 2H), 2.43-2.23 (m, 5H), 1.60- 1.48 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H) P30 PinkESIMS m/z 8.55 (s, 1H), 8.11- ¹⁹F NMR (376 Solid 623 ([M + H]⁺) 8.04 (m,2H), MHz, CDCl₃) 7.83-7.77 (m, δ −58.03 2H), 7.59 (dd, J = 8.2, 1.5 Hz,1H), 7.44-7.36 (m, 3H), 7.30 (dd, J = 7.7, 1.5 Hz, 1H), 7.27-7.25 (m,3H), 6.89 (dd, J = 7.8, 1.5 Hz, 1H), 3.87 (s, 2H), 3.51 (dh, J = 27.3,6.9 Hz, 2H), 2.87 (td, J = 7.0, 2.8 Hz, 2H), 1.31 (s, 9H) P31 Off- ESIMSm/z 8.55 (s, 1H), 8.09 ¹⁹F NMR (376 White 609 ([M + H]⁺) (d, J = 8.2 Hz,2H), MHz, CDCl₃) Solid 7.80 (d, J = 9.0 Hz, δ −58.03 2H), 7.43-7.35 (m,2H), 7.28 (s, 2H), 7.17 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.0, 2.0 Hz,1H), 6.94 (d, J = 7.9 Hz, 1H), 5.51 (t, J = 6.2 Hz, 1H), 3.91 (d, J =1.5 Hz, 2H), 3.52 (qd, J = 7.0, 2.6 Hz, 2H), 2.87 (t, J = 7.1 Hz, 2H),2.50-2.32 (m, 5H), 1.15 (t, J = 7.6 Hz, 3H) P33 Brown 105 ESIMS m/z 8.56(d, J = 0.6 ¹⁹F NMR (376 Solid (dec.) 641 ([M + H]⁺) Hz, 1H), 8.08 (dd,MHz, CDCl₃) J = 10.1, 8.2 Hz, δ −58.03, −110.63, 2H), 7.84-7.76 −110.66,−110.66 (m, 2H), 7.43- 7.37 (m, 2H), 7.30- 7.27 (m, 1H), 7.25-7.22 (m,1H), 7.11 (dd, J = 9.8, 2.6 Hz, 1H), 7.02 (dddd, J = 11.3, 7.3, 6.0, 2.9Hz, 2H), 5.31 (dd, J = 11.9, 8.5 Hz, 1H), 4.23-4.10 (m, 1H), 3.91 (t, J= 1.8 Hz, 2H), 3.06- 2.59 (m, 3H), 1.22-1.05 (m, 9H) P42 Off- ESIMS m/z8.56 (s, 1H), 8.13- ¹⁹F NMR (376 White 623 ([M + H]⁺) 8.03 (m, 2H), MHz,CDCl₃) Solid 7.83-7.75 (m, δ −58.03 2H), 7.42-7.27 (m, 6H), 7.25- 7.13(m, 1H), 5.42- 5.29 (m, 1H), 3.93 (d, J = 0.9 Hz, 2H), 3.04-2.83 (m,1H), 2.70 (td, J = 13.5, 7.8 Hz, 2H), 2.42 (q, J = 7.9 Hz, 2H), 2.12 (d,J = 5.3 Hz, 3H), 1.16 (td, J = 7.6, 2.1 Hz, 3H), 1.10 (dd, J = 6.7, 2.6Hz, 3H) P44 Yellow ESIMS m/z 8.55 (s, 1H), 8.15- ¹⁹F NMR (376 Solid 611([M + H]⁺) 8.04 (m, 2H), MHz, CDCl₃) 7.86-7.74 (m, δ −58.03 2H), 7.39(d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H),6.82 (d, J = 8.6 Hz, 2H), 5.52 (t, J = 6.2 Hz, 1H), 3.91 (s, 2H), 3.80(s, 3H), 3.53 (q, J = 6.9 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.11 (s,3H) P45 Brown ESIMS m/z 8.56 (d, J = 0.6 ¹⁹F NMR (376 Solid 625 ([M +H]⁺) Hz, 1H), 8.12- MHz, CDCl₃) 8.05 (m, 2H), 7.80 δ −58.03 (d, J = 9.0Hz, 2H), 7.44-7.35 (m, 2H), 7.30-7.27 (m, 2H), 7.02 (dd, J = 9.1, 7.1Hz, 1H), 6.84 (qd, J = 5.5, 4.6, 1.8 Hz, 2H), 5.38 (dd, J = 8.4, 5.7 Hz,1H), 3.96-3.84 (m, 3H), 3.82 (d, J = 0.7 Hz, 3H), 2.98 (ddd, J = 13.3,9.9, 5.4 Hz, 1H), 2.69 (td, J = 13.9, 7.9 Hz, 1H), 2.12 (d, J = 3.0 Hz,3H), 1.10 (dd, J = 6.7, 1.1 Hz, 3H) P47 Yellow ESIMS m/z 8.55 (s, 1H),8.09 ¹⁹F NMR (376 Oil 625 ([M + H]⁺) (d, J = 8.2 Hz, 2H), MHz, CDCl₃)7.79 (d, J = 9.0 Hz, δ −58.02 2H), 7.39 (ddt, J = 7.7, 1.9, 1.0 Hz, 2H),7.30-7.26 (m, 2H), 6.67 (s, 2H), 5.56 (t, J = 6.2 Hz, 1H), 3.92 (s, 2H),3.78 (s, 3H), 3.59-3.40 (m, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.08 (s, 6H)P49 Pink ESIMS m/z 8.55 (s, 1H), 8.14- ¹⁹F NMR (376 Solid 609 ([M + H]⁺)8.04 (m, 2H), MHz, CDCl₃) 7.83-7.74 (m, δ −58.03 2H), 7.39 (dd, J = 8.9,1.0 Hz, 2H), 7.28-7.24 (m, 3H), 7.23-7.18 (m, 1H), 6.88 (s, 1H), 5.52(t, J = 6.1 Hz, 1H), 3.91 (d, J = 1.6 Hz, 2H), 3.52 (p, J = 6.8 Hz, 2H),2.88 (t, J = 7.1 Hz, 2H), 2.48- 2.35 (m, 2H), 2.34 (s, 3H), 1.14 (t, J =7.6 Hz, 3H) P50 Off- ESIMS m/z 8.55 (s, 1H), 8.09 ¹⁹F NMR (376 White 609([M + H]⁺) (d, J = 8.2 Hz, 2H), MHz, CDCl₃) Solid 7.80 (d, J = 9.0 Hz, δ−58.03 2H), 7.46-7.34 (m, 2H), 7.33- 7.26 (m, 3H), 7.17 (dd, J = 15.0,7.5 Hz, 2H), 5.51 (t, J = 6.0 Hz, 1H), 3.94 (s, 2H), 3.52 (dp, J = 13.4,6.6 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.41 (qd, J = 7.6, 2.6 Hz, 2H),2.11 (s, 3H), 1.15 (t, J = 7.6 Hz, 3H) P51 Dark ESIMS m/z 8.55 (s, 1H),8.17- ¹⁹F NMR (376 Brown 609 ([M + H]⁺) 8.05 (m, 2H), MHz, CDCl₃) Oil7.85-7.71 (m, δ −58.02 2H), 7.44-7.34 (m, 3H), 7.32- 7.27 (m, 3H), 7.10-6.96 (m, 2H), 5.52 (t, J = 6.2 Hz, 1H), 3.90 (s, 2H), 3.60-3.44 (m, 2H),2.91 (dt, J = 23.2, 7.0 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H) P52 Tan ESIMSm/z 8.64 (s, 1H), 8.09 ¹⁹F NMR (376 Glassy 607 ([M + H]⁺) (d, J = 8.2Hz, 2H), MHz, CDCl₃) Foam 7.95-7.86 (m, δ −62.49 2H), 7.84-7.75 (m, 2H),7.32- 7.22 (m, 4H), 6.85 (dd, J = 1.8, 0.9 Hz, 1H), 5.51 (t, J = 6.2 Hz,1H), 3.92 (d, J = 1.8 Hz, 2H), 3.52 (ddt, J = 35.1, 13.6, 6.7 Hz, 2H),2.87 (t, J = 7.1 Hz, 2H), 2.62 (dq, J = 14.3, 7.2 Hz, 1H), 2.33 (d, J =0.7 Hz, 3H), 1.15 (dd, J = 6.9, 2.3 Hz, 6H) P53 Brown ESIMS m/z 8.65 (s,1H), 8.14- ¹⁹F NMR (376 Foam 623 ([M + H]⁺) 8.05 (m, 2H), MHz, CDCl₃)7.95-7.86 (m, δ −62.49 2H), 7.84-7.75 (m, 2H), 7.34- 7.27 (m, 3H), 6.99(dd, J = 8.7, 2.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 5.53 (t, J = 6.2Hz, 1H), 3.93 (d, J = 1.7 Hz, 2H), 3.77 (s, 3H), 3.53 (ddt, J = 29.0,13.7, 6.7 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 2.60 (p, J = 6.9 Hz, 1H),1.20- 1.06 (m, 6H) P57 Clear ESIMS m/z 8.55 (s, 1H), 8.11- ¹⁹F NMR (376Sticky 637 ([M + H]⁺) 8.05 (m, 2H), MHz, CDCl₃) Oil 7.83-7.76 (m, δ−58.02 2H), 7.41-7.34 (m, 2H), 7.33- 7.21 (m, 4H), 6.90- 6.77 (m, 1H),5.51 (t, J = 6.2 Hz, 1H), 4.10-4.03 (m, 1H), 3.64- 3.39 (m, 2H), 2.87(t, J = 7.1 Hz, 2H), 2.73-2.51 (m, 1H), 2.33 (q, J = 0.7 Hz, 3H), 1.73(dd, J = 7.3, 4.5 Hz, 3H), 1.14 (ddd, J = 7.1, 4.5, 2.9 Hz, 6H) P58Yellow ESIMS m/z 8.54 (d, J = 1.2 Oil 623 ([M + H]⁺) Hz, 1H), 8.06 (d, J= 8.2 Hz, 2H), 7.83- 7.73 (m, 2H), 7.42-7.34 (m, 2H), 7.25 (dt, J = 8.0,2.1 Hz, 3H), 7.19-7.09 (m, 1H), 6.87-6.77 (m, 1H), 5.18 (dt, J = 25.9,6.2 Hz, 1H), 4.24-3.93 (m, 1H), 3.64- 3.26 (m, 3H), 3.05- 2.63 (m, 4H),2.31 (d, J = 8.5 Hz, 3H), 1.26-1.11 (m, 9H) P59 White ESIMS m/z 8.53 (d,J = 13.4 ¹⁹F NMR (376 Solid 623 ([M + H]⁺) Hz, 1H), 8.13- MHz, CDCl₃)8.02 (m, 2H), 7.83- δ −58.03 7.73 (m, 2H), 7.42-7.27 (m, 2H), 7.26-7.17(m, 4H), 7.01 (dd, J = 59.3, 7.4 Hz, 1H), 6.86 (d, J = 1.3 Hz, 1H), 4.92(t, J = 6.1 Hz, 1H), 3.78-3.63 (m, 1H), 3.49 (td, J = 14.1, 13.0, 6.9Hz, 2H), 3.32 (dq, J = 13.4, 7.0 Hz, 1H), 3.07 (q, J = 6.0 Hz, 2H),2.99-2.73 (m, 3H), 2.50- 2.26 (m, 4H), 1.16 (dd, J = 8.2, 6.9 Hz, 6H)P64 White ESIMS m/z 8.55 (d, J = 1.8 ¹⁹F NMR (376 Solid 637 ([M + H]⁺)Hz, 1H), 8.14 (dd, MHz, CDCl₃) J = 8.2, 5.4 Hz, δ −58.03 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.85- 7.75 (m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.34-7.25(m, 3H), 7.20 (dd, J = 8.0, 3.5 Hz, 1H), 7.12-6.81 (m, 2H), 4.92 (d, J =6.4 Hz, 1H), 3.71- 3.16 (m, 5H), 3.08- 2.76 (m, 5H), 2.67-2.37 (m, 2H),2.30 (s, 3H), 1.22-1.08 (m, 6H) P65 Orange ESIMS m/z 8.57 (s, 1H), 8.15-¹⁹F NMR (376 Solid 621 ([M + H]⁺) 8.08 (m, 2H), MHz, CDCl₃) 7.81 (d, J =9.0 Hz, δ −58.03 2H), 7.43-7.29 (m, 5H), 7.23 (d, J = 1.8 Hz, 2H), 7.02-6.94 (m, 1H), 6.27 (d, J = 1.2 Hz, 1H), 3.76-3.62 (m, 2H), 2.98 (q, J =6.5 Hz, 2H), 2.80 (p, J = 6.9 Hz, 1H), 2.31 (s, 3H), 2.21 (d, J = 1.1Hz, 3H), 1.11 (dd, J = 19.2, 6.9 Hz, 6H) P66, Off- 122 ESIMS m/z8.57-8.52 (m, ¹⁹F NMR (376 P353 White (dec.) 651 ([M + H]⁺) 1H),8.13-8.02 MHz, CDCl₃) Powder (m, 2H), 7.84- δ −58.03 7.76 (m, 2H), 7.43-7.36 (m, 2H), 7.35-7.29 (m, 2H), 7.26 (s, 2H), 6.85 (dd, J = 15.7, 1.8Hz, 1H), 5.25 (dd, J = 23.9, 9.0 Hz, 1H), 4.21- 4.03 (m, 1H), 3.98- 3.85(m, 2H), 3.08-2.75 (m, 1H), 2.63 (ddq, J = 28.1, 14.0, 7.0 Hz, 1H),2.39-2.29 (m, 3H), 1.36- 0.89 (m, 12H) P74 White ESIMS m/z ¹H NMR (400MHz, ¹⁹F NMR (376 Solid 581 ([M + H]⁺), DMSO-d₆) δ 9.41 MHz, CDCl₃) 579([M − H]⁻) (s, 1H), 8.13-8.06 δ −56.96 (m, 2H), 7.98- 7.89 (m, 2H),7.72- 7.59 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.37-7.25 (m, 4H), 7.21(dt, J = 7.5, 1.1 Hz, 1H), 4.15-3.96 (m, 2H), 3.28 (dt, J = 8.3, 6.6 Hz,2H), 2.86-2.74 (m, 2H), 2.04 (s, 3H) P75 White ESIMS m/z ¹H NMR (400MHz, ¹⁹F NMR (376 Solid 595 ([M + H]⁺), DMSO-d₆) δ 9.41 MHz, CDCl₃) 593([M − H]⁻) (s, 1H), 8.16-8.04 δ −56.96 (m, 2H), 7.99- 7.87 (m, 2H),7.74- 7.59 (m, 3H), 7.48-7.33 (m, 3H), 7.34-7.24 (m, 2H), 7.22- 7.16 (m,1H), 4.18- 3.94 (m, 2H), 3.27 (td, J = 7.8, 7.2, 3.9 Hz, 2H), 2.84-2.76(m, 2H), 2.35 (q, J = 7.6 Hz, 2H), 1.04 (t, J = 7.6 Hz, 3H) P76 WhiteESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 609 ([M + H]⁺), DMSO-d₆) δ9.41 MHz, CDCl₃) 607 ([M − H]⁻) (s, 1H), 8.14-8.04 δ −56.96 (m, 2H),7.96- 7.88 (m, 2H), 7.68- 7.58 (m, 3H), 7.47-7.37 (m, 3H), 7.32-7.23 (m,2H), 7.16 (dd, J = 7.9, 1.3 Hz, 1H), 4.16-3.94 (m, 2H), 3.27 (q, J = 6.9Hz, 2H), 2.84- 2.75 (m, 2H), 2.63 (p, J = 6.8 Hz, 1H), 1.10-1.03 (m, 6H)P80 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 623 ([M + H]⁺),DMSO-d₆) δ 9.41 MHz, CDCl₃) 621 ([M − H]⁻) (s, 1H), 8.13-8.05 δ −56.97(m, 2H), 7.98- 7.89 (m, 2H), 7.69- 7.58 (m, 3H), 7.42 (t, J = 7.6 Hz,1H), 7.28 (dt, J = 7.7, 1.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.19-7.13(m, 1H), 7.02- 6.95 (m, 1H), 4.15- 3.93 (m, 2H), 3.28 (dt, J = 10.3, 7.3Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.30-2.20 (m, 5H), 1.51-1.33 (m, 2H),0.79 (t, J = 7.3 Hz, 3H) P81 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR(376 Solid 623 ([M + H]⁺), DMSO-d₆) δ 9.41 MHz, CDCl₃) 621 ([M − H]⁻)(s, 1H), 8.12-8.05 δ −56.96 (m, 2H), 7.96- 7.89 (m, 2H), 7.69- 7.59 (m,3H), 7.41 (t, J = 7.7 Hz, 1H), 7.33-7.25 (m, 2H), 7.23- 7.18 (m, 1H),6.96 (dd, J = 1.8, 0.9 Hz, 1H), 4.15- 3.94 (m, 2H), 3.27 (q, J = 6.9 Hz,2H), 2.86-2.73 (m, 2H), 2.63-2.53 (m, 1H), 2.25 (s, 3H), 1.04 (dd, J =6.9, 4.8 Hz, 6H) P83 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid609 ([M + H]⁺), DMSO-d₆) δ 9.41 MHz, CDCl₃) 607 ([M − H]⁻) (s, 1H),8.13-8.06 δ −56.97 (m, 2H), 7.97- 7.88 (m, 2H), 7.72- 7.59 (m, 3H), 7.41(t, J = 7.6 Hz, 1H), 7.31-7.24 (m, 2H), 7.20- 7.11 (m, 2H), 4.15 (d, J =1.7 Hz, 2H), 3.27 (dt, J = 8.1, 6.2 Hz, 2H), 2.84- 2.75 (m, 2H), 2.32(q, J = 7.6 Hz, 2H), 1.99 (d, J = 0.8 Hz, 3H), 1.03 (t, J = 7.6 Hz, 3H)P84 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 623 ([M + H]⁺),DMSO-d₆) δ 9.41 MHz, CDCl₃) 621 ([M − H]⁻) (s, 1H), 8.14-8.04 δ −56.97(m, 2H), 7.97- 7.88 (m, 2H), 7.68- 7.59 (m, 3H), 7.41 (t, J = 7.6 Hz,1H), 7.27 (dt, J = 7.7, 1.5 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.09-6.99(m, 2H), 4.13- 3.94 (m, 2H), 3.32- 3.23 (m, 2H), 2.85-2.75 (m, 2H), 2.58(p, J = 6.8 Hz, 1H), 2.32 (s, 3H), 1.05 (dd, J = 6.9, 3.6 Hz, 6H) P85White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 627 ([M + H]⁺),DMSO-d₆) δ 9.41 MHz, CDCl₃) 625 ([M − H]⁻) (s, 1H), 8.15-8.03 δ −56.97,−112.11 (m, 2H), 7.97- 7.87 (m, 2H), 7.69- 7.58 (m, 3H), 7.41 (t, J =7.6 Hz, 1H), 7.32-7.22 (m, 3H), 7.12 (td, J = 8.4, 2.9 Hz, 1H),4.15-3.93 (m, 2H), 3.32-3.23 (m, 2H), 2.85- 2.76 (m, 2H), 2.61 (tt, J =7.6, 3.8 Hz, 1H), 1.09-1.02 (m, 6H) P87 White ESIMS m/z ¹H NMR (400 MHz,¹⁹F NMR (376 Solid 611 ([M + H]⁺), DMSO-d₆) δ 9.41 MHz, CDCl₃) 609 ([M −H]⁻) (s, 1H), 8.17-8.02 δ −56.97 (m, 2H), 7.99- 7.88 (m, 2H), 7.71- 7.57(m, 3H), 7.47-7.39 (m, 1H), 7.29 (dt, J = 7.7, 1.4 Hz, 1H), 7.10 (d, J =8.6 Hz, 1H), 6.90-6.86 (m, 1H), 6.83 (ddd, J = 8.7, 2.8, 0.7 Hz, 1H),4.13- 3.92 (m, 2H), 3.76 (s, 3H), 3.28 (td, J = 8.1, 7.1, 4.4 Hz, 2H),2.86-2.76 (m, 2H), 1.99 (s, 3H) P92 Light ESIMS m/z ¹H NMR (400 MHz, ¹⁹FNMR (376 Yellow 595 ([M + H]⁺), DMSO-d₆) δ 9.38 MHz, CDCl₃) Solid 593([M − H]⁻) (s, 1H), 8.13-8.04 δ −56.96 (m, 2H), 8.04- 7.97 (m, 2H),7.68- 7.57 (m, 3H), 7.41-7.27 (m, 5H), 7.27-7.16 (m, 1H), 4.16- 3.95 (m,2H), 3.10- 2.95 (m, 2H), 2.60 (t, J = 7.7 Hz, 2H), 2.08 (s, 3H), 1.72(p, J = 7.1 Hz, 2H) P93 Light ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376Yellow 609 ([M + H]⁺), DMSO-d₆) δ 9.38 MHz, CDCl₃) Solid 607 ([M − H]⁻)(s, 1H), 8.11-8.04 δ −56.97 (m, 2H), 8.04- 7.97 (m, 2H), 7.66- 7.58 (m,3H), 7.45-7.37 (m, 2H), 7.37-7.27 (m, 3H), 7.22 (dt, J = 7.9, 1.0 Hz,1H), 4.17-3.95 (m, 2H), 3.04 (dp, J = 16.0, 6.4 Hz, 2H), 2.59 (t, J =7.7 Hz, 2H), 2.39 (q, J = 7.6 Hz, 2H), 1.82- 1.64 (m, 2H), 1.10 (td, J =7.3, 1.9 Hz, 3H) P94 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376Solid 623 ([M + H]⁺), DMSO-d₆) δ 9.38 MHz, CDCl₃) 621 ([M − H]⁻) (s,1H), 8.12-8.04 δ −56.97 (m, 2H), 8.04- 7.97 (m, 2H), 7.67- 7.57 (m, 3H),7.51-7.39 (m, 2H), 7.35-7.26 (m, 3H), 7.19 (dd, J = 7.8, 1.4 Hz, 1H),4.22-3.93 (m, 2H), 3.04 (p, J = 6.7 Hz, 2H), 2.68 (p, J = 6.8 Hz, 1H),2.59 (dd, J = 8.6, 6.8 Hz, 2H), 1.81- 1.62 (m, 2H), 1.18- 1.06 (m, 6H)P99 Light ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Yellow 637 ([M + H]⁺),DMSO-d₆) δ 9.38 MHz, CDCl₃) Solid 635 ([M − H]⁻) (s, 1H), 8.13-8.04 δ−56.97 (m, 2H), 8.04- 7.97 (m, 2H), 7.68- 7.57 (m, 3H), 7.39-7.29 (m,2H), 7.25 (d, J = 7.9 Hz, 1H), 7.22- 7.15 (m, 1H), 7.06- 6.98 (m, 1H),4.20-3.93 (m, 2H), 3.04 (p, J = 6.8 Hz, 2H), 2.59 (dd, J = 8.6, 6.7 Hz,2H), 2.28 (d, J = 10.1 Hz, 5H), 1.72 (p, J = 7.2 Hz, 2H), 1.48 (qd, J =7.4, 1.9 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H) P101 Light ESIMS m/z ¹H NMR(400 MHz, ¹⁹F NMR (376 Yellow 623 ([M + H]⁺), DMSO-d₆) δ 9.38 MHz,CDCl₃) Solid 621 ([M − H]⁻) (s, 1H), 8.14-8.04 δ −56.96 (m, 2H), 8.04-7.98 (m, 2H), 7.71- 7.59 (m, 3H), 7.38-7.27 (m, 3H), 7.25-7.17 (m, 2H),4.16 (d, J = 1.0 Hz, 2H), 3.04 (q, J = 6.6 Hz, 2H), 2.60 (t, J = 7.7 Hz,2H), 2.36 (q, J = 7.6 Hz, 2H), 2.05 (s, 3H), 1.73 (t, J = 7.4 Hz, 2H),1.09 (t, J = 7.6 Hz, 3H) P102 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR(376 Solid 637 ([M + H]⁺), DMSO-d₆) δ 9.38 MHz, CDCl₃) 635 ([M − H]⁻)(s, 1H), 8.13-8.04 δ −56.97 (m, 2H), 8.04- 7.96 (m, 2H), 7.67- 7.57 (m,3H), 7.37-7.29 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.13- 7.01 (m, 2H),4.17- 3.91 (m, 2H), 3.04 (p, J = 6.7 Hz, 2H), 2.60 (dt, J = 15.4, 7.4Hz, 3H), 2.34 (s, 3H), 1.72 (p, J = 7.1 Hz, 2H), 1.16-1.06 (m, 6H) P103Light ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Yellow 641 ([M + H]⁺),DMSO-d₆) δ 9.38 MHz, CDCl₃) Solid 639 ([M − H]⁻) (s, 1H), 8.15-8.04 δ−56.97, −112.12 (m, 2H), 8.04- 7.98 (m, 2H), 7.71- 7.59 (m, 3H),7.37-7.25 (m, 4H), 7.15 (td, J = 8.4, 2.9 Hz, 1H), 4.18-3.92 (m, 2H),3.04 (dq, J = 13.2, 6.6 Hz, 2H), 2.75-2.54 (m, 3H), 1.72 (p, J = 7.1 Hz,2H), 1.13- 1.05 (m, 6H) P105 Light ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR(376 Yellow 625 ([M + H]⁺), DMSO-d₆) δ 9.38 MHz, CDCl₃) Solid 623 ([M −H]⁻) (s, 1H), 8.14-8.04 δ −56.97 (m, 2H), 8.04- 7.96 (m, 2H), 7.71- 7.55(m, 3H), 7.38-7.29 (m, 2H), 7.13 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.9Hz, 1H), 6.85 (dd, J = 8.6, 2.9 Hz, 1H), 4.12- 3.93 (m, 2H), 3.78 (s,3H), 3.16-2.93 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.04 (s, 3H),1.80-1.63 (m, 2H) P118 Off ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 White595 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz, CDCl₃) Solid 593 ([M − H]⁻) (s,1H), 8.13-8.04 δ −56.96 (m, 2H), 7.92 (dd, J = 7.1, 1.4 Hz, 2H),7.68-7.58 (m, 3H), 7.46- 7.39 (m, 1H), 7.39- 7.27 (m, 4H), 7.27-7.20 (m,1H), 4.17-3.94 (m, 2H), 3.16- 2.96 (m, 2H), 2.63 (t, J = 7.7 Hz, 2H),2.09 (s, 3H), 1.74 (p, J = 7.3 Hz, 2H) P119 Off ESIMS m/z ¹H NMR (400MHz, ¹⁹F NMR (376 White 609 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz, CDCl₃)Solid 607 ([M − H]⁻) (s, 1H), 8.14-8.04 δ −56.97 (m, 2H), 7.92 (dd, J =6.3, 1.4 Hz, 2H), 7.68-7.56 (m, 3H), 7.47- 7.37 (m, 3H), 7.37- 7.26 (m,2H), 7.22 (d, J = 7.8 Hz, 1H), 4.21-3.92 (m, 2H), 3.16- 2.96 (m, 2H),2.62 (t, J = 7.7 Hz, 2H), 2.40 (q, J = 7.6 Hz, 2H), 1.74 (p, J = 7.1 Hz,2H), 1.10 (t, J = 7.3, 2.7 Hz, 3H) P120 Off ESIMS m/z ¹H NMR (400 MHz,¹⁹F NMR (376 White 623 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz, CDCl₃) Solid 621([M − H]⁻) (s, 1H), 8.16-8.04 δ −56.97 (m, 2H), 7.92 (tt, J = 3.1, 1.4Hz, 2H), 7.69-7.58 (m, 3H), 7.48 (dd, J = 7.9, 1.6 Hz, 1H), 7.46-7.38(m, 2H), 7.30 (td, J = 7.5, 1.6 Hz, 2H), 7.20 (dd, J = 7.8, 1.4 Hz, 1H),4.21- 3.93 (m, 2H), 3.06 (qd, J = 6.8, 3.5 Hz, 2H), 2.65 (dt, J = 26.1,7.3 Hz, 3H), 1.73 (p, J = 7.3 Hz, 2H), 1.09 (dt, J = 7.0, 3.6 Hz, 6H)P124 Off ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 White 637 ([M + H]⁺),DMSO-d₆) δ 9.40 MHz, CDCl₃) Solid 635 ([M − H]⁻) (s, 1H), 8.14-8.02 δ−56.97 (m, 2H), 7.92 (tt, J = 3.1, 1.4 Hz, 2H), 7.70-7.56 (m, 3H), 7.42(t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.29 (dt, J = 7.8, 1.5Hz, 1H), 7.23 (dd, J = 8.1, 1.9 Hz, 1H), 6.99 (dd, J = 1.9, 0.9 Hz, 1H),4.20-3.92 (m, 2H), 3.06 (qd, J = 6.9, 3.3 Hz, 2H), 2.71-2.54 (m, 3H),2.29 (s, 3H), 1.85-1.62 (m, 2H), 1.16- 1.03 (m, 6H) P125 Off ESIMS m/z¹H NMR (400 MHz, ¹⁹F NMR (376 White 637 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz,CDCl₃) Solid 635 ([M − H]⁻) (s, 1H), 8.15-8.03 δ −56.97 (m, 2H), 7.92(dt, J = 5.8, 1.6 Hz, 2H), 7.69-7.57 (m, 3H), 7.42 (dd, J = 8.3, 7.6 Hz,1H), 7.30 (dt, J = 7.6, 1.5 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.19(ddd, J = 7.8, 1.9, 0.8 Hz, 1H), 7.02 (dd, J = 1.8, 0.9 Hz, 1H), 4.20-3.89 (m, 2H), 3.06 (ddd, J = 12.1, 6.9, 4.9 Hz, 2H), 2.62 (t, J = 7.7Hz, 2H), 2.29 (d, J = 2.9 Hz, 5H), 1.74 (p, J = 7.3 Hz, 2H), 1.57- 1.39(m, 2H), 0.84 (t, J = 7.3 Hz, 3H) P127 Off ESIMS m/z ¹H NMR (400 MHz,¹⁹F NMR (376 White 623 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz, CDCl₃) Solid 621([M − H]⁻) (s, 1H), 8.12-8.05 δ −56.97 (m, 2H), 7.96- 7.89 (m, 2H),7.71- 7.58 (m, 3H), 7.41 (dd, J = 8.6, 7.3 Hz, 1H), 7.30 (t, J = 7.5 Hz,2H), 7.25-7.17 (m, 2H), 4.15 (d, J = 1.0 Hz, 2H), 3.06 (q, J = 6.7 Hz,2H), 2.63 (t, J = 7.7 Hz, 2H), 2.36 (q, J = 7.5 Hz, 2H), 2.05 (s, 3H),1.82-1.65 (m, 2H), 1.09 (t, J = 7.3, 3.2 Hz, 3H) P128 Off ESIMS m/z ¹HNMR (400 MHz, ¹⁹F NMR (376 White 637 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz,CDCl₃) Solid 635 ([M − H]⁻) (s, 1H), 8.14-8.04 δ −56.97 (m, 2H), 7.92(dp, J = 5.2, 1.6 Hz, 2H), 7.69-7.56 (m, 3H), 7.42 (t, J = 7.9 Hz, 1H),7.33- 7.23 (m, 2H), 7.14-7.01 (m, 2H), 4.17-3.92 (m, 2H), 3.05 (qd, J =6.9, 3.5 Hz, 2H), 2.68-2.56 (m, 3H), 2.34 (s, 3H), 1.80-1.65 (m, 2H),1.16- 1.08 (m, 6H) P129 Off ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376White 641 ([M + H]⁺), DMSO-d₆) δ 9.40 MHz, CDCl₃) Solid 639 ([M − H]⁻)(s, 1H), 8.15-8.04 δ −56.97, −112.13 (m, 2H), 7.92 (tt, J = 3.1, 1.4 Hz,2H), 7.69-7.58 (m, 3H), 7.42 (t, J = 7.8 Hz, 1H), 7.37- 7.25 (m, 3H),7.15 (ddd, J = 8.7, 8.1, 2.9 Hz, 1H), 4.18- 3.91 (m, 2H), 3.06 (qd, J =6.9, 3.4 Hz, 2H), 2.73- 2.56 (m, 3H), 1.83- 1.64 (m, 2H), 1.17-1.05 (m,6H) P131 Off ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 White 625 ([M +H]⁺), DMSO-d₆) δ 9.40 MHz, CDCl₃) Solid 623 ([M − H]−) (s, 1H),8.13-8.05 δ −56.97 (m, 2H), 7.93 (dd, J = 7.3, 1.4 Hz, 2H), 7.69-7.58(m, 3H), 7.42 (td, J = 7.4, 1.0 Hz, 1H), 7.30 (dt, J = 7.6, 1.5 Hz, 1H),7.13 (d, J = 8.6 Hz, 1H), 6.92 (dd, J = 2.8, 0.8 Hz, 1H), 6.86 (ddd, J =8.7, 3.0, 0.7 Hz, 1H), 4.16- 3.91 (m, 2H), 3.39 (q, J = 7.0 Hz, 1H),3.34 (s, 2H), 3.16- 2.96 (m, 2H), 2.64 (dd, J = 8.7, 6.7 Hz, 2H), 2.04(s, 3H), 1.74 (p, J = 7.3 Hz, 2H) P144 White ESIMS m/z 8.54 (s, 1H),8.08 ¹⁹F NMR (376 Foam 609 ([M + H]⁺) (d, J = 8.1 Hz, 2H), MHz, CDCl₃)7.85-7.75 (m, δ −58.02 2H), 7.42-7.36 (m, 3H), 7.36- 7.28 (m, 3H), 7.26(s, 1H), 7.13-7.07 (m, 1H), 5.39 (s, 1H), 4.00-3.82 (m, 2H), 3.25 (qd, J= 6.9, 4.2 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.15 (s, 3H), 1.77-1.61(m, 2H), 1.52 (d, J = 0.5 Hz, 2H) P145 White 82-88 ESIMS m/z 8.54 (s,1H), 8.08 Solid 623 ([M + H]⁺) (d, J = 8.2 Hz, 2H), 7.83-7.76 (m, 2H),7.47-7.35 (m, 5H), 7.32 (td, J = 7.4, 2.0 Hz, 1H), 7.24 (s, 1H), 7.07(dd, J = 7.8, 1.3 Hz, 1H), 5.39 (t, J = 6.1 Hz, 1H), 3.98- 3.81 (m, 2H),3.36-3.09 (m, J = 6.8 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.45 (qd, J =7.6, 1.8 Hz, 2H), 1.75- 1.61 (m, 2H), 1.52 (s, 2H), 1.17 (t, J = 7.6 Hz,3H) P146 White 89-92 ESIMS m/z 8.54 (s, 1H), 8.11- Solid 637 ([M + H]⁺)8.05 (m, 2H), 7.84-7.76 (m, 2H), 7.47-7.42 (m, 2H), 7.38 (dt, J = 8.0,1.0 Hz, 2H), 7.30 (ddd, J = 7.9, 5.6, 3.2 Hz, 1H), 7.25-7.22 (m, 2H),7.07-7.01 (m, 1H), 5.38 (t, J = 6.0 Hz, 1H), 4.04- 3.81 (m, 2H),3.33-3.16 (m, 2H), 2.67 (dt, J = 10.3, 7.2 Hz, 3H), 1.73-1.60 (m, 2H),1.60-1.46 (m, 2H), 1.17 (dd, J = 6.9, 3.2 Hz, 6H) P150 White 100-105ESIMS m/z 8.55 (s, 1H), 8.11- ¹⁹F NMR (376 Solid 651 ([M + H]⁺) 8.05 (m,2H), MHz, CDCl₃) 7.83-7.76 (m, δ −58.03 2H), 7.39 (dd, J = 9.0, 0.9 Hz,2H), 7.33 (d, J = 8.0 Hz, 1H), 7.26 (s, 3H), 6.86 (dd, J = 1.9, 0.9 Hz,1H), 5.43 (t, J = 6.1 Hz, 1H), 4.02-3.82 (m, 2H), 3.34-3.16 (m, J = 6.6Hz, 2H), 2.65 (dt, J = 10.6, 7.1 Hz, 3H), 2.35 (s, 3H), 1.75- 1.60 (m,2H), 1.60- 1.47 (m, 2H), 1.21-1.07 (m, 6H) P151 White 78-82 ESIMS m/z8.54 (s, 1H), 8.12- Solid 651 ([M + H]⁺) 8.05 (m, 2H), 7.84-7.75 (m,2H), 7.41-7.35 (m, 2H), 7.24 (d, J = 3.8 Hz, 3H), 7.22- 7.17 (m, 1H),6.90-6.85 (m, 1H), 5.41 (t, J = 6.1 Hz, 1H), 3.97- 3.80 (m, 2H), 3.36-3.13 (m, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.42-2.23 (m, 5H), 1.75- 1.61(m, 2H), 1.61- 1.48 (m, 4H), 0.89 (t, J = 7.3 Hz, 3H) P152 White ESIMSm/z 8.54 (s, 1H), 8.08 ¹⁹F NMR (376 Solid 623 ([M + H]⁺) (d, J = 8.1 Hz,2H), MHz, CDCl₃) 7.84-7.76 (m, δ −58.02 2H), 7.42-7.34 (m, 1H), 7.26 (s,4H), 7.20-7.12 (m, 2H), 5.40 (s, 1H), 3.92 (s, 2H), 3.25 (q, J = 6.8 Hz,2H), 2.67 (t, J = 7.5 Hz, 2H), 2.12 (d, J = 0.7 Hz, 6H), 1.66 (q, J =7.7 Hz, 2H), 1.52 (s, 2H) P153 White ESIMS m/z 8.54 (s, 1H), 8.12- ¹⁹FNMR (376 Foam 637 ([M + H]⁺) 8.05 (m, 2H), MHz, CDCl₃) 7.84-7.74 (m, δ−58.02 2H), 7.43-7.36 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H),7.18 (dd, J = 15.3, 7.6 Hz, 3H), 5.40 (s, 1H), 3.92 (s, 2H), 3.25 (q, J= 6.7 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.42 (dt, J = 8.9, 7.4 Hz, 2H),2.11 (s, 3H), 1.66 (p, J = 7.4 Hz, 2H), 1.59-1.47 (m, 2H), 1.16 (t, J =7.6 Hz, 3H) P154 White 101-108 ESIMS m/z 8.54 (s, 1H), 8.12- Solid 651([M + H]⁺) 8.04 (m, 2H), 7.84-7.75 (m, 2H), 7.43-7.35 (m, 2H), 7.25-7.21 (m, 3H), 7.11 (ddd, J = 8.1, 2.0, 0.8 Hz, 1H), 6.92 (d, J = 8.0 Hz,1H), 5.40 (t, J = 6.1 Hz, 1H), 3.97-3.79 (m, 2H), 3.37- 3.16 (m, 2H),2.65 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.73- 1.59 (m, 2H), 1.52 (s,3H), 1.16 (dd, J = 6.9, 2.7 Hz, 6H) P155 White ESIMS m/z 8.55 (s, 1H),8.12- ¹⁹F NMR (376 Solid 655 ([M + H]⁺) 8.05 (m, 2H), MHz, CDCl₃)7.84-7.75 (m, δ −58.03, −110.71 2H), 7.44-7.35 (m, 2H), 7.30- 7.21 (m,2H), 7.11 (dd, J = 9.9, 2.6 Hz, 1H), 7.08- 6.94 (m, 2H), 5.40 (t, J =6.1 Hz, 1H), 4.00-3.81 (m, 2H), 3.37-3.16 (m, 2H), 2.67 (t, J = 7.3 Hz,3H), 1.65 (q, J = 7.8 Hz, 2H), 1.55 (s, 2H), 1.16 (dd, J = 6.9, 5.1 Hz,6H) P156 White ESIMS m/z 8.55 (s, 1H), 8.12- ¹⁹F NMR (376 Solid 667([M + H]⁺) 8.04 (m, 2H), MHz, CDCl₃) 7.85-7.71 (m, δ −58.03 2H),7.42-7.36 (m, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.26 (s, 3H), 7.01 (dd, J =8.7, 2.7 Hz, 1H), 6.57 (d, J = 2.7 Hz, 1H), 5.44 (t, J = 6.1 Hz, 1H),3.98- 3.85 (m, 2H), 3.79 (s, 3H), 3.26 (hept, J = 6.7 Hz, 2H), 2.66 (t,J = 7.5 Hz, 2H), 2.63-2.56 (m, 1H), 1.65 (q, J = 7.6 Hz, 2H), 1.56 (s,2H), 1.14 (dd, J = 6.9, 4.4 Hz, 6H) P159 White 110-117 ESIMS m/z 8.64(s, 1H), 8.09 ¹⁹F NMR (376 Solid. 635 ([M + H]⁺) (d, J = 8.2 Hz, 2H),MHz, CDCl₃) 7.94-7.88 (m, δ −62.48 2H), 7.83-7.76 (m, 2H), 7.33 (d, J =8.0 Hz, 1H), 7.28- 7.23 (m, 3H), 6.89-6.83 (m, 1H), 5.44 (t, J = 6.1 Hz,1H), 4.00- 3.80 (m, 2H), 3.41- 3.15 (m, 2H), 2.77-2.53 (m, 3H),2.44-2.28 (m, 3H), 1.71- 1.61 (m, 2H), 1.59- 1.50 (m, 2H), 1.15 (d, J =6.9 Hz, 6H) P160 Yellow 107-113 ESIMS m/z 8.57 (s, 1H), 8.13- ¹⁹F NMR(376 Solid 647 ([M + H]⁺) 8.08 (m, 2H), MHz, CDCl₃) 7.83-7.77 (m, δ−58.02 2H), 7.47-7.42 (m, 2H), 7.39 (dt, J = 8.0, 1.0 Hz, 2H), 7.33 (d,J = 8.0 Hz, 1H), 7.26 (s, 1H), 6.89-6.85 (m, 1H), 5.78 (t, J = 6.2 Hz,1H), 4.01- 3.82 (m, 2H), 3.47 (qd, J = 6.6, 3.2 Hz, 2H), 2.64 (dq, J =10.9, 6.4 Hz, 3H), 2.34 (s, 3H), 1.21-1.09 (m, 6H) P170 White ESIMS m/z¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 609 ([M + H]⁺) DMSO-d₆) δ 9.40 MHz,CDCl₃) (s, 1H), 8.13-8.05 δ −56.96 (m, 2H), 7.92 (dt, J = 6.5, 1.5 Hz,2H), 7.68-7.60 (m, 2H), 7.57 (t, J = 5.9 Hz, 1H), 7.46- 7.37 (m, 1H),7.37- 7.25 (m, 4H), 7.25-7.17 (m, 1H), 4.13-3.92 (m, 2H), 3.04 (dp, J =19.5, 6.5 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.06 (s, 3H), 1.64-1.50 (m,2H), 1.50- 1.37 (m, 2H) P171 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR(376 Solid 623 ([M + H]⁺) DMSO-d₆) δ 9.40 MHz, CDCl₃) (s, 1H), 8.13-8.05δ −56.96 (m, 2H), 7.92 (ddt, J = 5.2, 2.9, 1.7 Hz, 2H), 7.68- 7.60 (m,2H), 7.56 (t, J = 5.9 Hz, 1H), 7.46-7.35 (m, 3H), 7.34-7.25 (m, 2H),7.20 (dt, J = 7.8, 0.9 Hz, 1H), 4.15-3.93 (m, 2H), 3.03 (dp, J = 16.6,6.5 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.37 (q, J = 7.6 Hz, 2H), 1.54(q, J = 7.7 Hz, 2H), 1.49-1.37 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H) P172White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 637 ([M + H]⁺)DMSO-d₆) δ 9.40 MHz, CDCl₃) (s, 1H), 8.13-8.04 δ −56.96 (m, 2H), 7.91(tt, J = 3.2, 1.5 Hz, 2H), 7.63 (ddt, J = 7.9, 1.9, 1.0 Hz, 2H), 7.55(t, J = 5.8 Hz, 1H), 7.47-7.37 (m, 3H), 7.32- 7.24 (m, 2H), 7.17 (dd, J= 7.9, 1.4 Hz, 1H), 4.14- 3.93 (m, 2H), 3.03 (qd, J = 6.8, 2.3 Hz, 2H),2.64 (td, J = 7.3, 4.2 Hz, 3H), 1.63-1.48 (m, 2H), 1.49-1.37 (m, 2H),1.13- 1.05 (m, 6H) P176 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376Solid 651 ([M + H]⁺) DMSO-d₆) δ 9.40 MHz, CDCl₃) (s, 1H), 8.14-8.04 δ−56.97 (m, 2H), 7.92 (dt, J = 3.9, 1.7 Hz, 2H), 7.67-7.60 (m, 2H), 7.57(t, J = 5.9 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.36-7.26 (m, 2H), 7.21(dd, J = 8.2, 1.8 Hz, 1H), 7.00-6.95 (m, 1H), 4.12-3.92 (m, 2H), 3.03(q, J = 7.4, 7.0 Hz, 2H), 2.61 (dt, J = 17.5, 7.2 Hz, 3H), 2.26 (s, 3H),1.66-1.49 (m, 2H), 1.49- 1.37 (m, 2H), 1.10- 1.01 (m, 6H) P179 WhiteESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 637 ([M + H]⁺) DMSO-d₆) δ9.40 MHz, CDCl₃) (s, 1H), 8.13-8.05 δ −56.96 (m, 2H), 7.97- 7.87 (m,2H), 7.68- 7.55 (m, 3H), 7.41 (dd, J = 8.2, 7.6 Hz, 1H), 7.28 (ddd, J =7.4, 4.4, 2.8 Hz, 2H), 7.22- 7.14 (m, 2H), 4.14 (d, J = 1.0 Hz, 2H),3.03 (q, J = 6.6 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.34 (q, J = 7.5 Hz,2H), 2.02 (s, 3H), 1.62- 1.49 (m, 2H), 1.50- 1.37 (m, 2H), 1.08-1.02 (m,3H) P180 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR (376 Solid 651 ([M +H]⁺) DMSO-d₆) δ 9.40 MHz, CDCl₃) (s, 1H), 8.13-8.06 δ −56.97 (m, 2H),7.92 (dp, J = 5.1, 1.6 Hz, 2H), 7.68-7.60 (m, 2H), 7.55 (t, J = 5.9 Hz,1H), 7.45- 7.37 (m, 1H), 7.28 (dt, J = 7.7, 1.5 Hz, 1H), 7.26- 7.20 (m,1H), 7.09- 7.00 (m, 2H), 4.13-3.91 (m, 2H), 3.10-2.96 (m, 2H), 2.61 (dt,J = 16.9, 7.1 Hz, 3H), 2.32 (s, 3H), 1.63-1.48 (m, 2H), 1.48-1.37 (m,2H), 1.11- 1.02 (m, 6H) P181 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR(376 Solid 655 ([M + H]⁺) DMSO-d₆) δ 9.40 MHz, CDCl₃) (s, 1H), 8.12-8.05δ −56.96, −112.17 (m, 2H), 7.96- 7.89 (m, 2H), 7.63 (dp, J = 7.7, 0.9Hz, 2H), 7.56 (t, J = 5.9 Hz, 1H), 7.46- 7.37 (m, 1H), 7.33-7.23 (m,3H), 7.12 (td, J = 8.4, 2.9 Hz, 1H), 4.14-3.91 (m, 2H), 3.11-2.96 (m,2H), 2.72- 2.56 (m, 3H), 1.55 (dq, J = 12.1, 7.7, 6.9 Hz, 2H), 1.44 (q,J = 7.6, 7.2 Hz, 2H), 1.12-1.03 (m, 6H) P182 White ESIMS m/z ¹H NMR (400MHz, ¹⁹F NMR (376 Solid 667 ([M + H]⁺) DMSO-d₆) δ 9.40 MHz, CDCl₃) (s,1H), 8.13-8.05 δ −56.96 (m, 2H), 7.92 (dt, J = 4.0, 1.8 Hz, 2H), 7.60(dd, J = 21.0, 7.3 Hz, 3H), 7.41 (t, J = 7.9 Hz, 1H), 7.36-7.25 (m, 2H),6.98 (dd, J = 8.7, 2.8 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 4.13-3.89 (m,2H), 3.71 (s, 3H), 3.03 (q, J = 7.5, 6.8 Hz, 2H), 2.60 (dt, J = 28.9,7.1 Hz, 3H), 1.65- 1.49 (m, 2H), 1.43 (dq, J = 13.4, 7.0 Hz, 2H), 1.05(dd, J = 16.4, 6.8 Hz, 6H) P205 Brown ESIMS m/z 8.55 (s, 1H), 8.13- ¹⁹FNMR (376 Solid 623 ([M + H]⁺) 8.03 (m, 2H), MHz, CDCl₃) 7.85-7.75 (m, δ−58.03 2H), 7.47-7.35 (m, 4H), 7.30- 7.23 (m, 3H), 7.01 (ddt, J = 7.6,6.7, 0.7 Hz, 1H), 5.39 (s, 1H), 3.97-3.87 (m, 2H), 3.65- 2.94 (m, 3H),2.74- 2.56 (m, 1H), 1.28 (dd, J = 6.9, 1.5 Hz, 3H), 1.21- 1.07 (m, 6H)P209 Brown ESIMS m/z 8.55 (s, 1H), 8.11- ¹⁹F NMR (376 Foam 637 ([M +H]⁺) 8.04 (m, 2H), MHz, CDCl₃) 7.83-7.74 (m, δ −58.02 2H), 7.43-7.35 (m,4H), 7.29- 7.18 (m, 3H), 7.00 (tt, J = 8.1, 1.1 Hz, 1H), 5.32 (d, J =16.6 Hz, 1H), 3.94- 3.85 (m, 2H), 3.79-3.54 (m, 1H), 3.27 (dddd, J =53.3, 13.9, 9.0, 5.2 Hz, 1H), 2.82- 2.56 (m, 2H), 1.82- 1.56 (m, 2H),1.19-1.02 (m, 6H), 0.86-0.74 (m, 3H) P364 Pink ESIMS m/z 8.56 (s, 1H),8.08 ¹⁹F NMR (376 Solid 651 ([M + H]⁺) (dd, J = 8.2, 6.4 MHz, CDCl₃) Hz,2H), 7.84- δ −58.02 7.76 (m, 2H), 7.39 (dq, J = 7.7, 1.1 Hz, 2H), 7.26(s, 4H), 6.81 (d, J = 7.6 Hz, 1H), 5.35 (d, J = 5.7 Hz, 1H), 3.94-3.84(m, 2H), 3.67 (ddt, J = 49.5, 13.1, 6.5 Hz, 1H), 3.39-3.15 (m, 1H),2.80- 2.53 (m, 2H), 2.30 (dt, J = 4.4, 0.7 Hz, 3H), 1.80-1.56 (m, 2H),1.10 (ddd, J = 18.9, 10.4, 6.8 Hz, 6H), 0.81 (t, J = 7.3 Hz, 3H) P679Brown ESIMS m/z 8.55 (s, 1H), 8.13- ¹⁹F NMR (376 Solid 653 ([M + H]⁺)8.03 (m, 2H), MHz, CDCl₃) 7.86-7.72 (m, δ −58.03 2H), 7.39 (ddd, J =8.0, 1.8, 0.9 Hz, 2H), 7.32-7.26 (m, 3H), 6.97 (ddd, J = 8.8, 4.4, 2.7Hz, 1H), 6.53 (dd, J = 6.4, 2.7 Hz, 1H), 5.49-5.28 (m, 1H), 3.91 (t, J =1.4 Hz, 2H), 3.75 (d, J = 3.1 Hz, 3H), 3.69-3.20 (m, 2H), 3.02 (dt, J =13.9, 6.9 Hz, 1H), 2.57 (h, J = 7.0 Hz, 1H), 1.29 (dd, J = 7.1, 1.5 Hz,3H), 1.16-1.04 (m, 6H) P683 Brown ESIMS m/z 8.55 (s, 1H), 8.13- ¹⁹F NMR(376 Foam 667 ([M + H]⁺) 8.02 (m, 2H), MHz, CDCl₃) 7.83-7.76 (m, δ−58.02 2H), 7.42-7.34 (m, 2H), 7.31- 7.19 (m, 3H), 6.95 (ddd, J = 8.5,5.4, 2.7 Hz, 1H), 6.52 (dd, J = 7.9, 2.7 Hz, 1H), 5.38 (s, 1H), 3.90 (t,J = 1.6 Hz, 2H), 3.79- 3.57 (m, 4H), 3.28 (dddd, J = 52.9, 13.9, 9.0,5.2 Hz, 1H), 2.81-2.47 (m, 2H), 1.81- 1.55 (m, 2H), 1.15- 1.00 (m, 6H),0.81 (t, J = 7.3 Hz, 3H) P1163 Brown ESIMS m/z 8.56 (s, 1H), 8.12- ¹⁹FNMR (376 Foam 655 ([M + H]⁺) 8.05 (m, 2H), MHz, CDCl₃) 7.84-7.77 (m, δ−58.02, −110.70, 2H), 7.43-7.36 −110.72 (m, 2H), 7.26- 7.18 (m, 2H),7.05 (ddd, J = 9.9, 4.8, 2.5 Hz, 1H), 7.01- 6.89 (m, 2H), 5.29 (t, J =6.2 Hz, 1H), 3.95-3.85 (m, 2H), 3.81-3.57 (m, 1H), 3.27 (dddd, J = 46.1,13.9, 9.1, 5.1 Hz, 1H), 2.81-2.50 (m, 2H), 1.67 (ddd, J = 56.8, 15.2,8.0 Hz, 2H), 1.18- 0.97 (m, 6H), 0.82 (t, J = 7.3 Hz, 3H) ^(a)All ¹H NMRdata measured in CDCl₃ at 400 MHz unless otherwise noted

TABLE 3c Analytical Data for Compounds in Table 2c. ¹³C NMR or No.Appearance Mp (° C.) ESIMS m/z ¹H NMR (δ)^(a) ¹⁹F NMR (δ) FB1 WhiteESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 596 [M]⁺ CDCl₃) δ 11.84 (s,(376 MHz, 1H), 9.72 (s, 1H), CDCl₃) δ −58.03 8.54 (s, 1H), 7.99 (s, 1H),7.95 (d, J = 8.8 Hz, 2H), 7.82-7.74 (m, 4H), 7.37 (ddd, J = 9.0, 2.1,1.0 Hz, 4H), 3.45-3.31 (m, 2H), 3.09 (dt, J = 22.4, 6.8 Hz, 1H), 2.91(t, J = 7.3 Hz, 2H), 2.42 (s, 3H), 2.32 (d, J = 0.8 Hz, 3H), 1.26-1.18(m, 6H) FB2 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 612 [M]⁺CDCl₃) δ 11.97 (s, (376 MHz, 1H), CDCl₃) δ −58.03 10.39-9.51 (m, 2H),8.54 (s, 1H), 7.99-7.90 (m, 3H), 7.81-7.75 (m, 3H), 7.37 (ddd, J = 7.8,2.1, 1.0 Hz, 3H), 7.24 (s, 1H), 3.77 (s, 3H), 3.36 (q, J = 6.7 Hz, 2H),3.04 (p, J = 6.7 Hz, 1H), 2.90 (t, J = 7.3 Hz, 2H), 2.41 (s, 3H), 1.23(t, J = 6.6 Hz, 6H) FB3 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR wax636 [M]⁺ CDCl₃) δ (376 MHz, 8.55 (s, 1H), 7.96 (d, J = 1.8 Hz, CDCl₃) δ−58.03 1H), 7.93-7.88 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.41-7.36 (m,3H), 7.31 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 6.85 (d, J =1.8 Hz, 1H), 5.56 (t, J = 6.3 Hz, 1H), 3.92 (d, J = 2.2 Hz, 2H),3.58-3.36 (m, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.64 (p, J = 6.8 Hz, 1H),2.38 (s, 3H), 2.36-2.31 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H) FB4 LightESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR Yellow 652 [M]⁺ CDCl₃) δ (376 MHz,solid 8.54 (s, 1H), CDCl₃) δ −58.03 7.99-7.95 (m, 1H), 7.90 (ddd, J =7.7, 2.0, 0.7 Hz, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.38 (dt, J = 8.0, 1.0Hz, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 6.99 (dd, J= 8.7, 2.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 5.57 (t, J = 6.3 Hz, 1H),3.93 (d, J = 2.0 Hz, 2H), 3.77 (s, 3H), 3.48 (dp, J = 25.0, 6.9 Hz, 2H),2.87 (t, J = 7.2 Hz, 2H), 2.61 (p, J = 6.8 Hz, 1H), 2.38 (s, 3H), 1.14(dd, J = 6.9, 3.5 Hz, 6H) FB5 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMRsolid 568 [M]⁺ CDCl₃) δ (376 MHz, 11.99 (s, 1H), CDCl₃) δ −58.03 10.16(s, 1H), 8.53 (d, J = 2.6 Hz, 1H), 7.95 (ddd, J = 14.0, 7.1, 1.7 Hz,2H), 7.80-7.73 (m, 2H), 7.40-7.32 (m, 5H), 7.25-7.15 (m, 3H), 3.50 (q, J= 6.8 Hz, 1H), 3.37 (dd, J = 7.5, 5.7 Hz, 1H), 2.95-2.86 (m, 1H), 2.83(t, J = 6.9 Hz, 1H), 2.65 (q, J = 7.5 Hz, 2H), 2.40 (s, 3H), 1.27-1.16(m, 3H) FB6 Pink solid ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 608 [M]⁺CDCl₃) δ (376 MHz, 8.55 (s, 1H), CDCl₃) δ −58.03 7.99-7.95 (m, 1H),7.94-7.88 (m, 1H), 7.83-7.75 (m, 2H), 7.43-7.35 (m, 4H), 7.33-7.28 (m,1H), 7.20 (d, J = 7.9 Hz, 1H), 7.07 (dd, J = 7.8, 1.3 Hz, 1H), 5.55 (t,J = 6.2 Hz, 1H), 3.93 (d, J = 1.6 Hz, 2H), 3.47 (ddd, J = 11.0, 7.0, 3.4Hz, 2H), 2.92-2.83 (m, 2H), 2.51-2.41 (m, 2H), 2.38 (s, 3H), 1.18 (t, J= 7.6 Hz, 3H) FB7 Pink solid ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 658 [M]⁺CDCl₃) δ (376 MHz, 8.54 (d, J = 3.2 Hz, 1H), CDCl₃) δ −58.03 8.00-7.89(m, 2H), 7.82-7.74 (m, 2H), 7.41-7.34 (m, 4H), 7.21 (dd, J = 14.3, 7.9Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 5.54 (t, J = 6.3 Hz, 1H), 3.93 (d, J= 1.9 Hz, 2H), 3.59-3.35 (m, 2H), 2.94-2.83 (m, 3H), 2.39 (d, J = 10.8Hz, 3H), 1.15 (t, J = 6.6 Hz, 6H) FB8 Orange oil ESIMS m/z ¹H NMR (400MHz, ¹⁹F NMR 640 [M]⁺ CDCl₃) δ (376 MHz, 8.55 (s, 1H), CDCl₃) δ −58.02,−117.98 7.92-7.82 (m, 3H), 7.79 (dd, J = 9.1, 1.3 Hz, 3H), 7.42-7.37 (m,2H), 7.33-7.28 (m, 1H), 6.89-6.78 (m, 1H), 5.54 (t, J = 6.2 Hz, 1H),3.92 (d, J = 1.7 Hz, 2H), 3.04 (t, J = 7.7 Hz, 2H), 2.91 (t, J = 7.0 Hz,2H), 2.73-2.61 (m, 1H), 2.33 (t, J = 0.7 Hz, 3H), 1.15 (dt, J = 6.8, 0.9Hz, 6H) FB9 Pink solid ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 656 [M]⁺CDCl₃) δ (376 MHz, 8.55 (s, 1H), CDCl₃) δ −58.02, −117.96 7.89-7.82 (m,2H), 7.79 (d, J = 9.1 Hz, 2H), 7.43-7.37 (m, 4H), 7.32 (d, J = 8.8 Hz,1H), 6.99 (dd, J = 8.7, 2.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 3.92 (d,J = 1.6 Hz, 2H), 3.77 (s, 3H), 3.52 (ddt, J = 30.6, 13.9, 6.7 Hz, 2H),2.91 (t, J = 7.0 Hz, 2H), 2.60 (p, J = 6.7 Hz, 1H), 1.14 (dd, J = 6.9,4.7 Hz, 6H) FB10 White ESIMS m/z ¹H NMR (400 MHz, ¹³C NMR solid 624([M + H]⁺) DMSO-d₆) δ (101 MHz, 9.39 (s, 1H), DMSO-d₆) δ 8.10-7.99 (m,5H), 165.51, 7.66-7.57 (m, 2H), 164.05, 7.43-7.39 (m, 2H), 162.06,7.39-7.32 (m, 2H), 151.48, 7.32-7.22 (m, 2H), 147.08, 4.06-3.62 (m, 2H),143.76, 3.09-2.90 (m, 4H), 2.24 (qd, J = 7.5, 141.37, 2.1 Hz, 2H),139.84, 0.98 (dt, J = 14.4, 135.72, 7.3 Hz, 6H) 134.04, 129.59, 129.44,129.22, 129.06, 129.01, 128.46, 126.92, 126.15, 122.60, 121.11, 44.12,34.76, 33.99, 23.50, 14.51, 13.81 FB11 Yellow ESIMS m/z ¹H NMR (400 MHz,¹³C NMR solid 668 ([M + H]⁺) CDCl₃) δ (101 MHz, 8.56 (s, 1H), 8.13 (d, J= 8.2 Hz, CDCl₃) δ 2H), 167.30, 7.80 (d, J = 9.0 Hz, 2H), 165.12,7.42-7.32 (m, 4H), 163.79, 7.05 (d, J = 8.7 Hz, 161.04, 1H), 6.91 (d, J= 2.8 Hz, 152.95, 1H), 148.80, 6.80 (dd, J = 8.6, 2.8 Hz, 148.55, 1H),141.92, 5.48 (t, J = 5.8 Hz, 139.76, 1H), 4.05-3.82 (m, 136.06, 2H),3.82 (s, 3H), 129.92, 3.34-3.18 (m, 2H), 129.70, 3.09 (td, J = 7.2,129.36, 2.3 Hz, 127.30, 2H), 2.66-2.50 (m, 126.04, 1H), 1.16-1.02 (m,122.85, 9H) 121.61, 113.01, 112.25, 100.44, 55.80, 45.46, 36.03, 35.27,29.26, 23.98, 23.89, 15.29 FB12 Yellow oil ESIMS m/z ¹H NMR (400 MHz,¹⁹F NMR 655 [M]⁺ CDCl₃) δ (376 MHz, 8.56 (s, 1H), 8.14 (d, J = 8.2 Hz,CDCl₃) δ −58.02, −115.49 2H), 7.80 (d, J = 9.0 Hz, 2H), 7.41-7.32 (m,5H), 7.14 (td, J = 8.3, 2.7 Hz, 1H), 6.85 (dd, J = 8.7, 2.7 Hz, 1H),5.52 (t, J = 5.8 Hz, 1H), 4.04-3.76 (m, 2H), 3.38-3.18 (m, 2H), 3.09(td, J = 7.2, 2.9 Hz, 2H), 2.58 (p, J = 6.8 Hz, 1H), 1.16-1.06 (m, 9H)FB13 Yellow oil ESIMS m/z ¹H NMR (400 MHz, (101 MHz, 656 ([M + H]⁺)CDCl₃) δ CDCl₃) δ 8.56 (s, 1H), 8.13 (d, J = 8.2 Hz, 166.98, 2H),164.98, 7.84-7.72 (m, 2H), 163.74, 7.42-7.31 (m, 4H), 162.68, 7.16-7.03(m, 2H), 152.58, 6.96 (ddd, J = 8.7, 7.6, 149.93, 2.9 Hz, 1H), 5.47 (t,148.79, J = 5.9 Hz, 1H), 141.93, 4.04-3.76 (m, 2H), 139.63, 3.35-3.17(m, 2H), 136.04, 3.09 (td, J = 7.2, 2.5 Hz, 130.80, 2H), 2.66-2.49 (m,130.71, 1H), 1.19-0.99 (m, 129.70, 9H) 129.40, 127.30, 122.85, 121.61,114.63, 114.36, 114.13, 45.42, 36.06, 35.24, 29.37, 23.86, 23.74, 15.28FB14 Yellow ESIMS m/z ¹H NMR (400 MHz, ¹³C NMR solid 638 ([M + H]⁺)CDCl₃) δ (101 MHz, 8.56 (s, 1H), CDCl₃) δ 8.17-8.10 (m, 2H), 166.95,7.86-7.72 (m, 2H), 165.08, 7.46-7.33 (m, 7H), 163.79, 7.17-7.05 (m, 1H),5.47 (t, J = 5.8 Hz, 152.72, 1H), 148.79, 4.06-3.75 (m, 2H), 147.10,3.34-3.16 (m, 2H), 141.93, 3.10 (td, 139.74, J = 7.2, 2.3 Hz, 136.07,2H), 2.64 (p, J = 6.9 Hz, 133.27, 1H), 130.62, 1.20-1.06 (m, 10H)129.71, 129.38, 128.93, 127.32, 127.26, 122.86, 121.62, 119.57, 77.80,45.46, 36.03, 35.29, 29.03, 24.04, 23.95, 15.29 FB15 Red oil ESIMS m/z1:1 Mixture of ¹³C NMR 677 ([M + H]⁺) diastereoisomers (151 MHz, ¹H NMR(600 MHz, CDCl₃) δ CDCl₃) δ 8.60 (d, J = 11.3 Hz, 173.06, 1H), 168.38,8.15-8.04 (m, 2H), 163.84, 7.89-7.78 (m, 161.44, 2H), 7.44 (dd, J = 8.7,148.68, 5.9 Hz, 2H), 145.96, 7.35-7.31 (m, 2H), 143.44, 7.30-7.26 (m,2H), 141.77, 6.87-6.73 (m, 1H), 136.97, 5.30 (dd, J = 37.0, 8.8 Hz,135.96, 1H), 132.82, 3.92-3.81 (m, 2H), 3.54 (q, J = 7.0 Hz, 131.29,1H), 129.14, 2.62 (td, J = 14.0, 7.2 Hz, 128.89, 1H), 128.64, 2.41-2.26(m, 4H), 128.19, 2.02-1.80 (m, 3H), 127.07, 1.77-1.45 (m, 3H), 126.78,1.34-1.10 (m, 6H), 122.74, 0.90 (dd, J = 155.3, 121.46, 6.8 Hz, 2H)53.43, 50.50, 36.05, 34.39, 33.22, 28.56, 26.41, 25.58, 24.18, 23.89,21.04 FB16 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 583 ([M + H]⁺)DMSO-d₆) δ (376 MHz, 11.91 (s, 1H), 9.95 (s, DMSO-d₆) δ 1H), 9.37 (s,1H), −56.97 8.11-7.94 (m, 4H), 7.66-7.56 (m, 2H), 7.44 (d, J = 8.0 Hz,1H), 7.36 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 1.9 Hz, 1H), 7.00 (d, J =8.0 Hz, 2H), 3.17 (q, J = 6.5 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.26(s, 3H), 2.15 (s, 3H), 1.64 (q, J = 7.6 Hz, 2H), 1.51 (q, J = 7.2 Hz,2H) FB17 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR foam 623 ([M + H]⁺)CDCl₃) δ (376 MHz, 8.54 (s, 1H), CDCl₃) δ −58.02 8.11-8.06 (m, 2H),7.83-7.76 (m, 2H), 7.38 (dd, J = 9.1, 1.0 Hz, 1H), 7.26 (s, 3H), 7.14(dd, J = 1.5, 0.8 Hz, 1H), 7.13-7.08 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H),5.41 (t, J = 6.1 Hz, 1H), 3.97-3.77 (m, 2H), 3.25 (qd, J = 6.9, 4.1 Hz,2H), 2.67 (t, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.10 (s, 3H), 1.73-1.61 (m,2H), 1.60-1.45 (m, 2H) FB18 Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMRsolid 527 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 11.98 (s, 1H), 10.24 (s,DMSO-d₆) δ 1H), 9.43 (s, 1H), −56.96 8.16-7.97 (m, 4H), 7.69-7.59 (m,3H), 7.59-7.50 (m, 2H), 7.44 (dt, J = 7.6, 1.5 Hz, 1H), 7.31-7.25 (m,1H), 7.20 (pd, J = 7.5, 1.9 Hz, 2H), 4.47 (d, J = 5.9 Hz, 2H), 2.22 (s,3H) FB19 Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 557 ([M +H]⁺) DMSO-d₆) δ (376 MHz, 11.76 (s, 1H), 10.19 (s, DMSO-d₆) δ 1H), 9.43(s, 1H), −56.95 8.13-8.06 (m, 3H), 8.03 (dt, J = 7.7, 1.4 Hz, 1H),7.68-7.60 (m, 2H), 7.58-7.49 (m, 2H), 7.44 (dt, J = 7.7, 1.5 Hz, 1H),7.38 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 2.9 Hz, 1H), 6.77 (dd, J = 8.7,2.9 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.75 (s, 3H), 2.17 (s, 3H) FB20Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 541 ([M + H]⁺)DMSO-d₆) δ (376 MHz, 12.01 (s, 1H), 10.27 (s, DMSO-d₆) δ 1H), 9.45 (s,1H), −56.96 8.15-8.08 (m, 3H), 8.06 (dt, J = 7.8, 1.4 Hz, 1H), 7.65(ddd, J = 7.9, 2.0, 1.0 Hz, 2H), 7.62-7.52 (m, 3H), 7.46 (dt, J = 7.8,1.5 Hz, 1H), 7.33-7.27 (m, 1H), 7.27-7.20 (m, 2H), 4.49 (d, J = 5.8 Hz,2H), 2.57 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H) FB21 Off-whiteESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 555 ([M + H]⁺) DMSO-d₆) δ (376MHz, 11.59 (s, 1H), 10.25 (s, DMSO-d₆) δ 1H), 9.45 (s, 1H), −56.978.15-8.08 (m, 3H), 8.06 (dt, J = 7.7, 1.4 Hz, 1H), 7.69-7.62 (m, 2H),7.59-7.52 (m, 2H), 7.46 (dt, J = 7.7, 1.4 Hz, 1H), 7.19 (dd, J = 8.0,6.9 Hz, 1H), 7.15-7.09 (m, 2H), 4.49 (d, J = 5.8 Hz, 2H), 2.56-2.48 (m,2H), 2.20 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H) FB22 Off-white ESIMS m/z ¹HNMR (400 MHz, ¹⁹F NMR solid 555 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 11.95(s, 1H), 10.28 (s, DMSO-d₆) δ 1H), 9.45 (s, 1H), −56.96 8.16-8.08 (m,3H), 7.68-7.62 (m, 2H), 7.61-7.51 (m, 2H), 7.50-7.40 (m, 3H), 7.37 (dd,J = 7.8, 1.6 Hz, 1H), 7.29 (td, J = 7.5, 1.5 Hz, 1H), 7.23 (td, J = 7.5,1.7 Hz, 1H), 4.49 (d, J = 5.8 Hz, 2H), 3.03 (hept, J = 6.5 Hz, 1H), 1.18(d, J = 6.8 Hz, 6H) FB23 Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMRsolid 569 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 11.85 (s, 1H), DMSO-d₆) δ10.36-10.12 (m, 1H), −56.96 9.45 (s, 1H), 8.16-8.08 (m, 3H), 8.06 (dt, J= 7.7, 1.4 Hz, 1H), 7.69-7.62 (m, 2H), 7.61-7.52 (m, 2H), 7.46 (dt, J =7.7, 1.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.19-7.14 (m, 1H), 7.08-6.99(m, 1H), 4.48 (d, J = 5.8 Hz, 2H), 2.98 (p, J = 6.9 Hz, 1H), 2.33 (s,3H), 1.17 (d, J = 6.8 Hz, 6H) FB24 Off-white ESIMS m/z ¹H NMR (400 MHz,¹⁹F NMR solid 573 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 11.83 (s, 1H), 10.31(s, DMSO-d₆) δ 1H), 9.45 (s, 1H), −56.97, −114.35 8.16-8.08 (m, 3H),8.06 (dt, J = 7.6, 1.5 Hz, 1H), 7.69-7.63 (m, 2H), 7.60-7.52 (m, 2H),7.46 (dt, J = 7.7, 1.5 Hz, 1H), 7.41 (dd, J = 8.8, 5.6 Hz, 1H), 7.18(dd, J = 10.4, 3.0 Hz, 1H), 7.06 (td, J = 8.5, 3.0 Hz, 1H), 4.49 (d, J =5.8 Hz, 2H), 3.00 (pd, J = 6.8, 1.6 Hz, 1H), 1.17 (d, J = 6.8 Hz, 6H)FB25 Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 569 ([M + H]⁺)DMSO-d₆) δ (376 MHz, 11.90 (s, 1H), 10.25 (s, DMSO-d₆) δ 1H), 9.45 (s,1H), −56.96 8.15-8.08 (m, 3H), 8.06 (dt, J = 7.8, 1.6 Hz, 1H), 7.69-7.62(m, 2H), 7.56 (dt, J = 11.3, 6.7 Hz, 2H), 7.46 (dt, J = 7.8, 1.5 Hz,1H), 7.24 (d, J = 8.1 Hz, 2H), 7.14-7.07 (m, 1H), 4.49 (d, J = 5.8 Hz,2H), 2.98 (p, J = 6.9 Hz, 1H), 2.28 (s, 3H), 1.15 (d, J = 6.8 Hz, 6H)FB26 Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 589 ([M + H]⁺)DMSO-d₆) δ (376 MHz, 12.02 (s, 1H), 10.37 (s, DMSO-d₆) δ 1H), 9.45 (s,1H), −56.96 8.15-8.08 (m, 3H), 8.06 (dt, J = 7.7, 1.5 Hz, 1H), 7.70-7.62(m, 2H), 7.62-7.52 (m, 3H), 7.46 (dt, J = 7.8, 1.4 Hz, 1H), 7.42-7.31(m, 2H), 4.49 (d, J = 5.8 Hz, 2H), 3.01 (p, J = 6.8 Hz, 1H), 1.17 (d, J= 6.8 Hz, 6H) FB27 Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid567 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 9.40 (s, 1H), 8.22 (t, J = 6.3 Hz,DMSO-d₆) δ 1H), −56.96 8.13-8.03 (m, 2H), 8.01-7.93 (m, 2H), 7.63 (dq, J= 7.9, 1.0 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.40-7.28 (m, 4H),7.28-7.21 (m, 1H), 4.35-4.19 (m, 2H), 4.17-3.96 (m, 2H), 2.10 (s, 3H)FB28 Light ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR orange 597 ([M + H]⁺)DMSO-d₆) δ (376 MHz, solid 9.40 (s, 1H), 8.22 (t, J = 6.3 Hz, DMSO-d₆) δ1H), −56.96 8.11-8.03 (m, 2H), 8.02-7.93 (m, 2H), 7.69-7.59 (m, 2H),7.45 (t, J = 7.6 Hz, 1H), 7.33 (dt, J = 7.7, 1.5 Hz, 1H), 7.15 (d, J =8.7 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.86 (dd, J = 8.7, 2.9 Hz, 1H),4.35-4.19 (m, 2H), 4.15-3.93 (m, 2H), 3.78 (s, 3H), 2.05 (s, 3H) FB29White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 581 ([M + H]⁺) DMSO-d₆) δ(376 MHz, 9.40 (s, 1H), 8.22 (t, J = 6.3 Hz, DMSO-d₆) δ 1H), −56.968.12-8.03 (m, 2H), 8.01-7.93 (m, 2H), 7.68-7.59 (m, 2H), 7.48-7.38 (m,3H), 7.37-7.28 (m, 2H), 7.24 (dt, J = 7.8, 1.0 Hz, 1H), 4.36-4.18 (m,2H), 4.18-3.95 (m, 2H), 2.40 (q, J = 7.6 Hz, 2H), 1.10 (td, J = 7.3, 1.6Hz, 3H) FB30 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 595 ([M +H]⁺) DMSO-d₆) δ (376 MHz, 9.40 (s, 1H), 8.25 (t, J = 6.3 Hz, DMSO-d₆) δ1H), −56.96 8.15-8.02 (m, 2H), 8.01-7.94 (m, 2H), 7.63 (ddd, J = 7.9,2.1, 1.0 Hz, 2H), 7.49-7.42 (m, 1H), 7.37-7.27 (m, 2H), 7.26-7.15 (m,2H), 4.26 (d, J = 6.3 Hz, 2H), 4.18 (d, J = 1.2 Hz, 2H), 2.37 (q, J =7.5 Hz, 2H), 2.06 (s, 3H), 1.12-1.07 (m, 3H) FB31 Light ESIMS m/z ¹H NMR(400 MHz, ¹⁹F NMR yellow 595 ([M + H]⁺) DMSO-d₆) δ (376 MHz, solid 9.40(s, 1H), 8.22 (t, J = 6.3 Hz, DMSO-d₆) δ 1H), −56.97 8.13-8.02 (m, 2H),8.00-7.92 (m, 2H), 7.70-7.57 (m, 2H), 7.53-7.39 (m, 3H), 7.37-7.26 (m,2H), 7.21 (dd, J = 7.8, 1.4 Hz, 1H), 4.35-4.19 (m, 2H), 4.18-3.96 (m,2H), 2.68 (h, J = 7.0 Hz, 1H), 1.13-1.04 (m, 6H) FB32 Light ESIMS m/z ¹HNMR (400 MHz, ¹⁹F NMR orange 609 ([M + H]⁺) DMSO-d₆) δ (376 MHz, solid9.40 (s, 1H), 8.21 (t, J = 6.3 Hz, DMSO-d₆) δ 1H), −56.97 8.11-8.02 (m,2H), 8.01-7.91 (m, 2H), 7.67-7.59 (m, 2H), 7.44 (td, J = 7.5, 0.9 Hz,1H), 7.31 (dt, J = 7.7, 1.4 Hz, 1H), 7.29-7.24 (m, 1H), 7.16-7.02 (m,2H), 4.35-4.18 (m, 2H), 4.18-3.93 (m, 2H), 2.63 (p, J = 6.8 Hz, 1H),2.34 (s, 3H), 1.12-1.02 (m, 6H) FB33 Off-white ESIMS m/z ¹H NMR (400MHz, ¹⁹F NMR solid 613 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 9.40 (s, 1H),8.22 (t, J = 6.3 Hz, DMSO-d₆) δ 1H), −56.96, −112.09 8.12-8.02 (m, 2H),7.96 (dd, J = 7.4, 1.4 Hz, 2H), 7.69-7.59 (m, 2H), 7.44 (td, J = 7.4,1.0 Hz, 1H), 7.37-7.28 (m, 3H), 7.15 (td, J = 8.4, 2.9 Hz, 1H),4.37-4.19 (m, 2H), 4.19-3.93 (m, 2H), 2.67 (tt, J = 7.4, 5.7 Hz, 1H),1.16-1.03 (m, 6H) FB34 Off-white ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMRsolid 609 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 9.40 (s, 1H), 8.24 (t, J = 6.3Hz, DMSO-d₆) δ 1H), −56.98 8.13-8.03 (m, 2H), 7.96 (dt, J = 9.2, 1.5 Hz,2H), 7.69-7.58 (m, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.40-7.27 (m, 2H),7.28-7.20 (m, 1H), 7.01 (dd, J = 1.7, 0.9 Hz, 1H), 4.35-4.19 (m, 2H),4.18-3.94 (m, 2H), 2.63 (p, J = 6.8 Hz, 1H), 2.28 (s, 3H), 1.12-1.03 (m,6H) FB35 Light ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR yellow 629 ([M + H]⁺)DMSO-d₆) δ (376 MHz, solid 9.40 (s, 1H), 8.27 (t, J = 6.3 Hz, DMSO-d₆) δ1H), −56.97 8.11-8.03 (m, 2H), 8.01-7.92 (m, 2H), 7.69-7.58 (m, 2H),7.57-7.47 (m, 2H), 7.47-7.39 (m, 2H), 7.32 (dt, J = 7.7, 1.5 Hz, 1H),4.41-4.20 (m, 2H), 4.19-3.88 (m, 2H), 2.69 (p, J = 6.8 Hz, 1H),1.17-1.05 (m, 6H) FB36 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid599 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 11.80 (s, 1H), 9.96 (s, DMSO-d₆) δ1H), 9.39 (s, 1H), −56.96 8.13-8.04 (m, 2H), 7.98 (t, J = 1.6 Hz, 1H),7.94 (dt, J = 7.7, 1.4 Hz, 1H), 7.62 (dq, J = 9.1, 1.0 Hz, 2H), 7.44 (t,J = 7.6 Hz, 1H), 7.40-7.31 (m, 2H), 7.01 (t, J = 5.6 Hz, 1H), 6.82 (d, J= 2.9 Hz, 1H), 6.75 (dd, J = 8.7, 2.9 Hz, 1H), 3.74 (s, 3H), 3.18 (q, J= 6.4 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.14 (s, 3H), 1.65 (q, J = 7.6Hz, 2H), 1.52 (p, J = 6.9 Hz, 2H) FB37 White ESIMS m/z ¹H NMR (400 MHz,¹⁹F NMR solid 631 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 12.08 (s, 1H), 10.15(s, DMSO-d₆) δ 1H), 9.41 (s, 1H), −56.96 8.13-8.07 (m, 2H), 8.00 (t, J =1.7 Hz, 1H), 7.96 (dt, J = 7.7, 1.4 Hz, 1H), 7.64 (dq, J = 7.9, 1.0 Hz,2H), 7.59 (d, J = 2.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.41-7.30 (m,3H), 7.05 (t, J = 5.7 Hz, 1H), 3.21 (q, J = 6.5 Hz, 2H), 2.98 (p, J =6.8 Hz, 1H), 2.74 (t, J = 7.6 Hz, 2H), 1.68 (q, J = 7.6 Hz, 2H), 1.54(p, J = 6.9 Hz, 2H), 1.15 (d, J = 6.8 Hz, 6H) FB38 White ESIMS m/z ¹HNMR (400 MHz, ¹⁹F NMR solid 639 ([M + H]⁺) DMSO-d₆) δ (376 MHz, 9.40 (s,1H), DMSO-d₆) δ 8.13-8.04 (m, 2H), 7.92 (dt, J = 6.6, −56.96 1.5 Hz,2H), 7.63 (dp, J = 7.9, 1.0 Hz, 2H), 7.56 (t, J = 5.9 Hz, 1H), 7.46-7.37(m, 1H), 7.30 (dt, J = 7.7, 1.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.89(dd, J = 2.9, 0.8 Hz, 1H), 6.83 (ddd, J = 8.7, 2.9, 0.7 Hz, 1H),4.11-3.90 (m, 2H), 3.76 (s, 3H), 3.03 (dh, J = 19.9, 6.5 Hz, 2H), 2.65(t, J = 7.6 Hz, 2H), 2.02 (s, 3H), 1.64-1.50 (m, 2H), 1.50-1.37 (m, 2H)FB39 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR solid 671 ([M + H]⁺)DMSO-d₆) δ (376 MHz, 9.40 (s, 1H), DMSO-d₆) δ 8.13-8.04 (m, 2H), 7.92(ddt, −56.97 J = 3.8, 2.9, 1.4 Hz, 2H), 7.67-7.57 (m, 3H), 7.53-7.45 (m,2H), 7.45-7.37 (m, 2H), 7.28 (dt, J = 7.7, 1.5 Hz, 1H), 4.14-3.87 (m,2H), 3.04 (qd, J = 6.9, 2.9 Hz, 2H), 2.73-2.56 (m, 3H), 1.55 (dq, J =8.9, 7.2 Hz, 2H), 1.49-1.37 (m, 2H), 1.11-1.02 (m, 6H) FB40 Brown ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR glassy 671 ([M + H]⁺) CDCl₃) δ (376 MHz,foam 8.54 (s, 1H), CDCl₃) δ −58.02 8.12-8.03 (m, 2H), 7.84-7.74 (m, 2H),7.39 (ddt, J = 6.9, 2.8, 1.7 Hz, 3H), 7.34 (d, J = 8.5 Hz, 1H), 7.27 (s,2H), 7.05 (d, J = 2.1 Hz, 1H), 5.47 (t, J = 6.1 Hz, 1H), 3.92 (d, J =1.5 Hz, 2H), 3.53 (dp, J = 26.7, 6.7 Hz, 2H), 2.88 (t, J = 6.6 Hz, 2H),2.64 (p, J = 6.9 Hz, 1H), 1.14 (dd, J = 8.8, 6.9 Hz, 6H) FB41 Yellow oilESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 637 ([M + H]⁺) CDCl₃) δ (376 MHz,8.56 (s, 1H), 8.08 (d, J = 8.2 Hz, CDCl₃) δ −58.03 2H), 7.82-7.79 (m,3H), 7.39 (dt, J = 8.1, 1.0 Hz, 3H), 7.24 (d, J = 3.7 Hz, 2H), 7.16 (dd,J = 8.0, 1.8 Hz, 1H), 6.76 (dd, J = 1.8, 0.9 Hz, 1H), 5.18 (t, J = 6.2Hz, 1H), 3.46 (ddt, J = 36.9, 13.6, 6.7 Hz, 2H), 3.19-3.10 (m, 3H),3.04-2.89 (m, 1H), 2.85 (t, J = 7.0 Hz, 2H), 2.62 (p, J = 7.0 Hz, 1H),2.30 (t, J = 0.7 Hz, 3H), 1.12 (dd, J = 6.9, 4.6 Hz, 6H) FB42 Brown oilESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 658 ([M + H]⁺) CDCl₃) δ (376 MHz,8.56 (s, 1H), 8.08 (dd, J = 15.7, CDCl₃) δ −58.03 8.2 Hz, 2H), 7.80 (d,J = 9.0 Hz, 2H), 7.44-7.34 (m, 4H), 7.29 (d, J = 8.2 Hz, 1H), 7.26-7.21(m, 1H), 7.08 (dd, J = 13.8, 2.1 Hz, 1H), 5.34 (dd, J = 15.4, 8.5 Hz,1H), 3.96-3.84 (m, 2H), 3.01 (dd, J = 13.4, 5.6 Hz, 1H), 2.87 (dd, J =13.5, 5.8 Hz, 1H), 2.77 (dd, J = 13.5, 7.0 Hz, 1H), 2.71-2.57 (m, 1H),1.20-1.06 (m, 9H) FB43 Peach ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR glassy431 ([M + H]⁺) CDCl₃) δ 8.56 (s, (376 MHz, foam 1H), 8.20-8.10 (m,CDCl₃) δ −58.03 2H), 7.84-7.74 (m, 2H), 7.39 (dt, J = 8.0, 1.0 Hz, 2H),7.36-7.29 (m, 2H), 3.68 (tdd, J = 8.3, 5.3, 4.4 Hz, 1H), 2.98-2.77 (m,2H), 1.76-1.64 (m, 1H), 1.61-1.51 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H) FB44Tan 90 (dec.) ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR glassy 672 ([M + H]⁺)CDCl₃) δ (376 MHz, foam 8.56 (s, 1H), 8.07 (dd, J = 18.4, CDCl₃) δ−58.02 8.2 Hz, 2H), 7.84-7.75 (m, 2H), 7.43-7.34 (m, 4H), 7.31-7.27 (m,1H), 7.25-7.19 (m, 1H), 7.08 (dd, J = 12.4, 2.1 Hz, 1H), 5.26 (t, J =9.2 Hz, 1H), 4.02-3.93 (m, 1H), 3.91 (dd, J = 3.7, 1.1 Hz, 2H),2.96-2.73 (m, 2H), 2.63 (h, J = 6.8 Hz, 1H), 1.42-1.28 (m, 2H),1.20-1.09 (m, 6H), 0.90 (dt, J = 24.3, 7.4 Hz, 3H) FB45 Yellow oil ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR 637 ([M + H]⁺) CDCl₃) δ (376 MHz, 8.55 (d,J = 0.8 Hz, CDCl₃) δ −58.02 1H), 8.11-8.02 (m, 2H), 7.84-7.75 (m, 2H),7.43-7.35 (m, 2H), 7.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.30-7.21 (m, 3H),6.87 (ddd, J = 12.7, 1.8, 0.9 Hz, 1H), 5.39 (dd, J = 16.1, 8.5 Hz, 1H),4.20-4.11 (m, 1H), 3.91 (dd, J = 2.5, 1.8 Hz, 2H), 3.02-2.85 (m, 1H),2.81-2.58 (m, 2H), 2.35 (d, J = 7.6 Hz, 3H), 1.15 (ddd, J = 6.9, 4.3,1.5 Hz, 6H), 1.09 (t, J = 6.6 Hz, 3H) FB46 Off-white ESIMS m/z ¹H NMR(400 MHz, ¹⁹F NMR foam 637 ([M + H]⁺) CDCl₃) δ 8.55 (d, J = 0.6 Hz, (376MHz, 1H), CDCl₃) δ −58.02 8.13-8.02 (m, 2H), 7.84-7.75 (m, 2H),7.43-7.36 (m, 2H), 7.36-7.31 (m, 1H), 7.30-7.21 (m, 3H), 6.90-6.84 (m,1H), 5.37 (dd, J = 15.4, 8.4 Hz, 1H), 4.20-4.11 (m, 1H), 3.98-3.84 (m,2H), 2.94 (ddd, J = 51.6, 13.4, 5.5 Hz, 1H), 2.76 (dd, J = 13.5, 7.1 Hz,1H), 2.70-2.58 (m, 1H), 2.35 (d, J = 7.9 Hz, 3H), 1.17-1.14 (m, 6H),1.09 (t, J = 6.8 Hz, 3H) FB47 Brown oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹FNMR 637 ([M + H]⁺) CDCl₃) δ (376 MHz, 8.56 (d, J = 0.8 Hz, 1H), CDCl₃) δ−58.03 8.07 (dd, J = 11.2, 8.2 Hz, 2H), 7.85-7.77 (m, 2H), 7.43-7.36 (m,2H), 7.34 (d, J = 8.8 Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.21 (m, 1H),7.02 (dt, J = 8.8, 3.1 Hz, 1H), 6.58 (dd, J = 11.5, 2.7 Hz, 1H), 5.37(dd, J = 14.6, 8.5 Hz, 1H), 4.12 (m, 2H), 3.96-3.88 (m, 2H), 3.79 (d, J= 5.1 Hz, 2H), 3.05-2.55 (m, 3H), 1.18-1.10 (m, 9H) FB48 Brown oil ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR 637 ([M + H]⁺) CDCl₃) δ 8.56 (d, J = 0.9Hz, (376 MHz, 1H), CDCl₃) δ −58.03 8.07 (dd, J = 10.2, 8.2 Hz, 2H),7.84-7.77 (m, 2H), 7.43-7.36 (m, 2H), 7.28 (dd, J = 7.4, 1.4 Hz, 1H),7.26-7.22 (m, 2H), 7.17-7.07 (m, 1H), 6.94 (dd, J = 11.5, 8.0 Hz, 1H),5.36 (dd, J = 14.4, 8.4 Hz, 1H), 4.22-4.10 (m, 1H), 3.91 (t, J = 1.8 Hz,2H), 3.05-2.60 (m, 3H), 2.40 (d, J = 2.5 Hz, 3H), 1.21-1.05 (m, 9H) FB49Brown oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 658 ([M + H]⁺) CDCl₃) δ(376 MHz, 8.56 (s, 1H), 8.09 (ddd, CDCl₃) δ −58.03 J = 9.2, 5.5, 3.8 Hz,2H), 7.80 (d, J = 9.0 Hz, 2H), 7.38 (ddt, J = 8.7, 6.8, 2.6 Hz, 3H),7.32 (dd, J = 8.5, 4.3 Hz, 1H), 7.29 (d, J = 7.7 Hz, 2H), 7.03 (dd, J =6.6, 2.1 Hz, 1H), 5.39 (s, 1H), 3.91 (d, J = 2.1 Hz, 2H), 3.65-3.22 (m,2H), 3.02 (d, J = 10.0 Hz, 1H), 2.62 (tt, J = 14.6, 7.6 Hz, 1H),1.32-1.27 (m, 3H), 1.20-1.04 (m, 6H) FB50 Clear oil ESIMS m/z ¹H NMR(400 MHz, ¹⁹F NMR 628 ([M + H]⁺) CDCl₃) δ (376 MHz, 8.68-8.61 (m, 1H),CDCl₃) δ −62.49 8.15-8.04 (m, 2H), 7.95-7.85 (m, 2H), 7.85-7.77 (m, 2H),7.45-7.37 (m, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.31-7.27 (m, 2H), 7.06 (d,J = 2.1 Hz, 1H), 5.52 (t, J = 6.2 Hz, 1H), 3.93 (d, J = 1.6 Hz, 2H),3.53 (ddt, J = 25.1, 13.6, 6.7 Hz, 2H), 2.88 (t, J = 6.9 Hz, 2H),2.71-2.57 (m, 1H), 1.20-1.07 (m, 6H) FB51 Pale 99 (dec.) ESIMS m/z ¹HNMR (400 MHz, ¹⁹F NMR orange 637 ([M + H]⁺) CDCl₃) δ 8.56 (d, J = 8.0Hz, (376 MHz, foam 1H), CDCl₃) δ −58.02 8.00 (d, J = 8.1 Hz, 2H), 7.82(d, J = 8.9 Hz, 2H), 7.46-7.36 (m, 3H), 7.31 (dd, J = 8.2, 6.4 Hz, 1H),6.93 (d, J = 1.1 Hz, 1H), 6.75 (d, J = 8.2 Hz, 2H), 3.93 (d, J = 5.1 Hz,2H), 3.63-3.34 (m, 1H), 3.20 (ddd, J = 13.5, 9.2, 6.6 Hz, 1H), 2.99 (s,3H), 2.77-2.68 (m, 1H), 2.63-2.51 (m, 2H), 2.35 (d, J = 0.7 Hz, 3H),1.21-1.12 (m, 6H) FB52 Brown oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 651([M + H]⁺) CDCl₃) δ 8.56 (d, J = 4.5 Hz, (376 MHz, 1H), CDCl₃) δ −58.038.12-8.02 (m, 2H), 7.83-7.75 (m, 2H), 7.43-7.35 (m, 2H), 7.30 (d, J =8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 1.3 Hz, 1H), 5.21(s, 1H), 3.95 (d, J = 2.6 Hz, 2H), 3.28-2.96 (m, 2H), 2.66 (p, J = 6.8Hz, 1H), 2.32 (s, 3H), 1.25 (d, J = 5.1 Hz, 6H), 1.14 (ddd, J = 10.9,6.9, 4.7 Hz, 6H) FB53 Brown ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR glassy651 ([M + H]⁺) CDCl₃) δ 8.56 (s, (376 MHz, foam 1H), 8.09 (d, J = 8.4Hz, CDCl₃) δ −58.03 2H), 7.80 (d, J = 9.0 Hz, 2H), 7.44-7.35 (m, 4H),7.28 (d, J = 8.1 Hz, 1H), 7.24-7.19 (m, 1H), 6.86-6.77 (m, 1H), 5.27 (s,1H), 3.89 (d, J = 0.9 Hz, 2H), 3.56 (dd, J = 13.7, 7.2 Hz, 1H), 3.41(dd, J = 13.7, 5.9 Hz, 1H), 2.59 (p, J = 6.9 Hz, 1H), 2.31 (d, J = 0.7Hz, 3H), 1.35 (d, J = 2.5 Hz, 6H), 1.11 (dd, J = 11.5, 6.9 Hz, 6H) FB54Red soild 95 (dec.) ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 651 ([M + H]⁺)CDCl₃) δ 8.56 (d, J = 8.6 Hz, (376 MHz, 1H), CDCl₃) δ −58.02 8.04 (dd, J= 40.0, 8.1 Hz, 2H), 7.85-7.76 (m, 2H), 7.44-7.35 (m, 3H), 7.35-7.28 (m,1H), 7.25-7.19 (m, 1H), 6.98-6.84 (m, 1H), 6.70 (d, J = 8.2 Hz, 1H),3.93 (dd, J = 5.9, 4.2 Hz, 2H), 3.61-2.45 (m, 7H), 2.40-2.25 (m, 3H),1.32-1.07 (m, 9H) FB55 Yellow oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 609([M + H]⁺) CDCl₃) δ 8.55 (d, J = 0.7 Hz, (376 MHz, 1H), CDCl₃) δ −58.038.15-8.04 (m, 2H), 7.84-7.74 (m, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.28 (d,J = 2.3 Hz, 1H), 7.25-7.01 (m, 3H), 6.91-6.78 (m, 1H), 5.28-5.13 (m,1H), 4.25-3.89 (m, 1H), 3.62-3.28 (m, 2H), 3.04-2.73 (m, 3H), 2.70-2.37(m, 3H), 2.32 (d, J = 7.6 Hz, 3H), 1.29-1.13 (m, 6H) FB56 Yellow oilESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 609 ([M + H]⁺) CDCl₃) δ (376 MHz,8.59-8.47 (m, 1H), CDCl₃) δ −58.03 8.13-8.01 (m, 2H), 7.80 (dd, J = 9.8,3.0 Hz, 2H), 7.46-7.34 (m, 3H), 7.28 (d, J = 1.7 Hz, 2H), 7.13 (s, 1H),7.08-6.99 (m, 1H), 6.92 (dd, J = 16.0, 8.0 Hz, 1H), 5.18 (d, J = 6.4 Hz,1H), 4.26-3.92 (m, 1H), 3.59-3.27 (m, 2H), 3.02-2.76 (m, 3H), 2.62-2.38(m, 2H), 2.37-2.26 (m, 3H), 1.37-1.08 (m, 6H) FB57 Yellow oil ESIMS m/z¹H NMR (400 MHz, ¹⁹F NMR 627 ([M + H]⁺) CDCl₃) δ (376 MHz, 8.57-8.52 (m,1H), CDCl₃) δ −58.03, −112.99 8.14-8.02 (m, 2H), 7.84-7.75 (m, 2H),7.44-7.34 (m, 2H), 7.27-7.22 (m, 2H), 7.15-6.78 (m, 4H), 5.13 (d, J =19.1 Hz, 1H), 4.41-4.16 (m, 1H), 3.62-3.28 (m, 2H), 3.20-2.73 (m, 4H),1.32-1.10 (m, 9H) FB58 Yellow oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 611([M + H]⁺) CDCl₃) δ (376 MHz, 8.58-8.48 (m, 1H), CDCl₃) δ −58.038.16-8.00 (m, 2H), 7.87-7.67 (m, 2H), 7.43-7.17 (m, 6H), 7.08-6.90 (m,1H), 6.83-6.69 (m, 1H), 5.21 (s, 1H), 4.25-3.92 (m, 1H), 3.77 (d, J =14.8 Hz, 3H), 3.64-3.27 (m, 2H), 3.06-2.75 (m, 3H), 2.24-2.10 (m, 3H),1.28-1.11 (m, 3H) FB59 Clear oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 595([M + H]⁺) CDCl₃) δ 8.55 (dd, (376 MHz, J = 4.6, 1.1 Hz, CDCl₃) δ −58.031H), 8.12-8.04 (m, 2H), 7.87-7.70 (m, 2H), 7.46-7.34 (m, 3H), 7.28 (d, J= 7.9 Hz, 2H), 7.22-7.02 (m, 3H), 5.20 (t, J = 6.1 Hz, 1H), 4.22-4.11(m, 1H), 3.55-3.31 (m, 3H), 2.95 (dd, J = 11.0, 8.4 Hz, 1H), 2.87-2.80(m, 1H), 2.18 (d, J = 12.6 Hz, 6H), 1.16 (d, J = 6.3 Hz, 3H) FB60 YellowESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR foam 623 ([M + H]⁺) CDCl₃) δ (376MHz, 8.58-8.53 (m, 1H), CDCl₃) δ −58.03 8.13-8.01 (m, 2H), 7.84-7.75 (m,2H), 7.39 (dd, J = 9.1, 3.2 Hz, 2H), 7.28-7.23 (m, 3H), 7.18-7.12 (m,1H), 7.02 (dt, J = 8.1, 2.2 Hz, 1H), 6.89 (dd, J = 14.0, 8.0 Hz, 1H),5.24-5.08 (m, 1H), 4.24-3.91 (m, 1H), 3.63-3.29 (m, 3H), 3.04-2.74 (m,3H), 2.35 (d, J = 4.0 Hz, 3H), 1.34-1.06 (m, 9H) FB61 Brown oil ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR 663 ([M + H]⁺) CDCl₃) δ 8.56 (d, J = 7.7Hz, (376 MHz, 1H), CDCl₃) δ −58.02 8.11-7.95 (m, 2H), 7.85-7.75 (m, 2H),7.40 (td, J = 4.3, 1.2 Hz, 3H), 7.32-7.21 (m, 2H), 6.98-6.82 (m, 1H),6.73-6.65 (m, 1H), 5.87-5.38 (m, 1H), 5.15 (ddd, J = 13.8, 3.7, 1.6 Hz,1H), 4.99-4.67 (m, 1H), 4.03-3.96 (m, 1H), 3.94 (d, J = 5.4 Hz, 2H),3.64-3.47 (m, 1H), 3.36-3.12 (m, 2H), 2.98-2.63 (m, 2H), 2.59-2.51 (m,1H), 2.38-2.29 (m, 3H), 1.22-1.09 (m, 6H) FB62 Red- ESIMS m/z ¹H NMR(400 MHz, ¹⁹F NMR orange oil 677 ([M + H]⁺) CDCl₃) δ 8.56 (d, J = 8.5Hz, (376 MHz, 1H), CDCl₃) δ −58.02 8.13-7.94 (m, 2H), 7.85-7.75 (m, 2H),7.44-7.22 (m, 5H), 6.97-6.80 (m, 1H), 6.71-6.63 (m, 1H), 3.94 (dd, J =6.0, 4.4 Hz, 2H), 3.78-3.47 (m, 1H), 3.42-3.17 (m, 3H), 3.03-2.87 (m,1H), 2.81-2.55 (m, 2H), 2.33 (t, J = 1.1 Hz, 3H), 1.22-1.08 (m, 6H),1.09-0.94 (m, 1H), 0.62-0.44 (m, 2H), 0.31-0.17 (m, 2H) FB63 Red oilESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 649 ([M + H]⁺) CDCl₃) δ 8.56 (d, J =2.1 Hz, (376 MHz, 1H), CDCl₃) δ −58.03 8.19-8.00 (m, 2H), 7.83-7.75 (m,2H), 7.44-7.34 (m, 3H), 7.28 (s, 1H), 7.26-7.16 (m, 2H), 6.89 (s, 1H),5.63 (s, 1H), 3.93 (d, J = 2.5 Hz, 2H), 3.19 (d, J = 13.9 Hz, 1H), 2.75(d, J = 13.9 Hz, 1H), 2.61 (dd, J = 13.8, 7.0 Hz, 1H), 2.30 (s, 3H),1.13 (dd, J = 13.3, 6.8 Hz, 6H), 0.97-0.64 (m, 4H) FB64 Yellow oil ESIMSm/z ¹H NMR (400 MHz, ¹⁹F NMR 641 ([M + H]⁺) CDCl₃) δ 8.56 (s, (376 MHz,1H), 8.13-8.05 (m, CDCl₃) δ −58.03, −159.92, −160.90 2H), 7.85-7.74 (m,2H), 7.44-7.35 (m, 2H), 7.32 (dd, J = 8.1, 4.9 Hz, 1H), 7.29-7.25 (m,3H), 6.92-6.81 (m, 1H), 6.31 (dd, J = 55.6, 11.8 Hz, 1H), 5.62 (s, 1H),3.54 (ddt, J = 32.1, 13.7, 6.7 Hz, 2H), 2.88 (t, J = 7.0 Hz, 2H),2.73-2.48 (m, 1H), 2.37-2.30 (m, 3H), 1.15 (ddd, J = 9.6, 6.8, 2.8 Hz,6H) FB65 Clear oil ESIMS m/z ¹H NMR (400 MHz, 597 ([M + H]⁺) CDCl₃) δ8.56 (d, J = 7.8 Hz, 1H), 8.21-8.01 (m, 2H), 7.80 (dd, J = 10.0, 3.1 Hz,2H), 7.46-7.35 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 7.9 Hz,1H), 7.13 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 5.40 (d, J = 6.2 Hz, 1H),3.59 (p, J = 7.1 Hz, 2H), 3.14 (dt, J = 13.5, 6.7 Hz, 1H), 2.95 (q, J =6.3, 5.5 Hz, 2H), 2.46-2.22 (m, 6H), 1.16 (dd, J = 35.5, 6.9 Hz, 6H)FB66 Clear oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 611 ([M + H]⁺) CDCl₃)δ 11.53 (s, (376 MHz, 1H), CDCl₃) δ −58.02 8.64-8.52 (m, 1H), 8.24-7.97(m, 2H), 7.86-7.73 (m, 4H), 7.49-7.18 (m, 4H), 7.17-6.97 (m, 1H), 5.40(t, J = 6.1 Hz, 1H), 3.71-3.46 (m, 2H), 3.28-2.78 (m, 5H), 2.29 (d, J =18.6 Hz, 3H), 2.17 (d, J = 2.5 Hz, 3H), 1.42-1.12 (m, 6H) FB67 Clear oilESIMS m/z ¹H NMR (400 MHz, 639 ([M + H]⁺) CDCl₃) δ 10.16 (t, J = 5.6 Hz,1H), 8.55 (d, J = 2.6 Hz, 1H), 8.06 (dd, J = 8.3, 2.0 Hz, 2H), 7.85-7.74(m, 2H), 7.39 (dq, J = 8.0, 1.1 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.13(d, J = 7.8 Hz, 1H), 6.65-6.55 (m, 1H), 5.21 (t, J = 6.1 Hz, 1H), 3.59(tt, J = 12.6, 6.7 Hz, 2H), 3.32-2.99 (m, 2H), 2.99-2.76 (m, 3H), 2.27(d, J = 0.8 Hz, 2H), 2.17 (s, 3H), 1.88-1.84 (m, 2H), 1.11 (dd, J = 6.9,3.2 Hz, 6H) FB68 Pale ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR yellow 651([M + H]⁺) CDCl₃) δ 8.55 (s, (376 MHz, foam 1H), 8.08 (d, J = 8.2 Hz,CDCl₃) δ −58.03 2H), 7.83-7.76 (m, 3H), 7.44-7.38 (m, 2H), 7.33-7.20 (m,3H), 6.85 (dd, J = 1.9, 0.9 Hz, 1H), 5.54 (t, J = 6.2 Hz, 1H), 3.51(ddt, J = 35.0, 13.7, 6.7 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H), 2.64 (hept,J = 6.9 Hz, 1H), 2.33 (s, 3H), 1.73 (d, J = 2.3 Hz, 6H), 1.14 (dd, J =11.2, 6.8 Hz, 6H) FB69 White ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR foam 649([M + H]⁺) CDCl₃) δ 8.55 (s, (376 MHz, 1H), CDCl₃) δ −58.02 8.13-8.02(m, 2H), 7.84-7.73 (m, 2H), 7.42-7.35 (m, 2H), 7.33-7.20 (m, 4H), 6.89(dd, J = 1.9, 0.9 Hz, 1H), 5.57 (t, J = 6.2 Hz, 1H), 3.68-3.34 (m, 2H),2.86 (t, J = 7.1 Hz, 2H), 2.67 (hept, J = 6.9 Hz, 1H), 2.32 (s, 3H),1.77 (q, J = 4.4 Hz, 2H), 1.50-1.39 (m, 2H), 1.15 (dd, J = 10.5, 6.8 Hz,6H) FB70 Clear ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR colorless 701 ([M +H]⁺) CDCl₃) δ 8.55 (s, (376 MHz, oil 1H), CDCl₃) δ −58.03 8.13-8.01 (m,2H), 7.88-7.71 (m, 2H), 7.45-7.35 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H),7.29-7.22 (m, 3H), 6.87 (dd, J = 1.9, 0.9 Hz, 1H), 5.65 (t, J = 6.2 Hz,1H), 3.69-3.37 (m, 2H), 2.92-2.75 (m, 3H), 2.33 (s, 3H), 1.18 (dd, J =6.9, 5.0 Hz, 6H) FB71 Yellow oil ESIMS m/z ¹H NMR (400 MHz, ¹⁹F NMR 701([M + H]⁺) CDCl₃) δ 8.56 (d, J = 1.1 Hz, (376 MHz, 1H), CDCl₃) δ −58.018.21-8.10 (m, 2H), 7.84-7.75 (m, 2H), 7.48 (dd, J = 8.3, 6.1 Hz, 2H),7.44-7.36 (m, 2H), 7.35-7.29 (m, 1H), 7.29-7.22 (m, 1H), 6.85 (t, J =2.0 Hz, 1H), 5.86 (dt, J = 25.1, 6.3 Hz, 1H), 5.12 (ddd, J = 14.0, 8.2,6.1 Hz, 1H), 4.04-3.74 (m, 4H), 2.61 (ddq, J = 13.6, 10.1, 6.4 Hz, 1H),2.33 (s, 3H), 1.20-1.05 (m, 6H). FB72 White 180-185 ¹H NMR (400 MHz,solid CDCl₃) δ 8.55 (s, 1H), 8.08 (dd, J = 8.2, 1.0 Hz, 2H), 7.85-7.74(m, 2H), 7.45-7.35 (m, 2H), 7.33-7.20 (m, 4H), 6.87-6.80 (m, 1H), 5.54(t, J = 5.9 Hz, 1H), 4.13 (d, J = 6.5 Hz, 1H), 3.70 (d, J = 1.1 Hz, 1H),3.65-3.53 (m, 1H), 3.53-3.40 (m, 1H), 2.87 (t, J = 7.0 Hz, 2H),2.68-2.54 (m, 1H), 2.33 (s, 3H), 1.49-1.38 (m, 6H), 1.14 (td, J = 6.7,4.2 Hz, 6H) ^(a)All ¹H NMR data measured in CDCl₃ at 400 MHz unlessotherwise noted

BAW and CL Rating Table % Control (or Mortality) Rating 50-100 A Morethan 0-Less than 50 B Not Tested C No activity noticed in this bioassayD

GPA & YFM Rating Table % Control (or Mortality) Rating 80-100 A Morethan 0-Less than 80 B Not Tested C No activity noticed in this bioassayD

TABLE ABC Biological Results (F) Insect species No. BAW CL GPA YFM F1 AA D C F2 A A B A F3 A A B C F4 A A C C F5 A A A A F5A A A C C F6 A A B AF7 A A B A F8 A A D C F9 A A D A F10 A A B A F11 A A D C F12 A A D C F13A A D C F14 A A D A F15 A A C C F16 A A C C F17 A A C C F18 A A C C F19A A C C F20 A A C A F21 A A D A F22 A A D C F23 A A D C F24 A A D C F25A A D C F26 A A C C F27 A A D C F28 A A D C F29 A A D A F30 A A D C F31A A D C F32 A A D C F33 A A D C F34 A A D C F35 A C C C

TABLE ABC (P) Biological Results Insect species No. BAW CL GPA YFM P1 AA C C P2, P532 A A C C P3, P1172 A A C C P5 A A C C P6 A A C C P7 A A CC P8, P852 A A C C P14 A A C C P15 A A C C P20 C A C C P26 A A C A P27 AA C A P28 A A D A P29 A A C A P30 A A C A P31 A A C A P33 A A C A P42 AA C A P44 A A D A P45 A A C A P47 A A C A P49 A A C A P50 A A C A P51 AA B A P52 A A D A P53 A A C A P57 A A C A P58 A A C C P59 A A C C P64 AA C C P65 A A C A P66, P353 A A C A P74 A A C C P75 A A C C P76 A A C CP80 A A C C P81 C A C C P83 A A C C P84 A A C C P85 A A C C P87 A A C CP92 A A C C P93, P510 A A C C P94, P197 A A C C P99, P830 A A C C P101 BA C D P102 A A C C P103, P1150 A A C C P105 A A C C P118 A A C C P119 AA C C P120 A A C C P124 A A C C P125 A A C C P127 A A C C P128 A A C CP129 A A C C P131 A A C C P144 A A C A P145, P522 A A D A P146, P208 A AC A P150, P363 A A B A P151, P842 A A C A P152, P1481 D A C A P153 D A CD P154 A A C B P155, P1162 A A C A P156, P682 A A C A P159 A A B A P160A A C B P170 D A C C P171 A A C C P172 A A C C P176 A A C C P179 D D C CP180 D A C C P181 A A C C P182 A A C C P205 A A C A P209 A C C A P364 AA C C P679 A A C A P683 A C C A P1163 A C C D

TABLE ABC (PC) Biological Results Insect species No. BAW CL GPA YFM PC1A A C C PC2 C C C C PC3 A A C C PC5 A A C C PC6 C C C C PC7 A A C C PC8A A C C PC14 C C C C PC15 A A C C PC16 C C C C PC74 A A C C PC75 D C C CPC76 C C C C PC80 C C C C PC81 C C C C PC83 A A C C PC84 C C C C PC85 CC C C PC87 D A C C PC92 A A C C PC93 A A C C PC94 A A C C PC99 A D C CPC101 A A C C PC102 A D C C PC103 B D C C PC105 D D C C PC118 D C C CPC119 A A C C PC120 A A C C PC124 A A C C PC125 A A C C PC127 A A C CPC128 A A C C PC129 A A C C PC131 A A C C PC144 A A C C PC145 A A C CPC146 A A C C PC150 A A C C PC151 A A C C PC152 A A C C PC153 D A D BPC154 A A C C PC155 A A C C PC156 A A C C PC159 A A C C PC160 A A C DPC170 B A C C PC171 B A C C PC172 A A C C PC176 B A C C PC179 B A C CPC180 B D C C PC181 B D C C PC182 D A C C

TABLE ABC (FB) Biological Results Insect species No. BAW CL GPA YFM FB1A A C C FB2 A A C C FB3 A A C C FB4 A A C C FB5 A A C C FB6 A A C C FB7A A C C FB8 A A C C FB9 A A C C FB10 A A C C FB11 B A C C FB12 A A C CFB13 B A C C FB14 A A C C FB15 A A C C FB16 D A C C FB17 A A C A FB18 AA C C FB19 A A C C FB20 A A C C FB21 A A C C FB22 A A C C FB23 A A C CFB24 A A C C FB25 A A C C FB26 A A C C FB27 A A C C FB28 A A C C FB29 AA C C FB30 A A C C FB31 A A C C FB32 A A C C FB33 A A C C FB34 A A C CFB35 A A C C FB36 B A C C FB37 B B C C FB38 B A C C FB39 A A C C FB40 AA C A FB41 A A C A FB42 A A C A FB43 A A B A FB44 A A B A FB45 A A C CFB46 A A C C FB47 A A C A FB48 A A C A FB49 A A C A FB50 A A C C FB51 AA C A FB52 A A C C FB53 A A C B FB54 A A C A FB55 A A C C FB56 A A C AFB57 A A C A FB58 A A C A FB59 A A C A FB60 A A C A FB61 A A C A FB62 AA C A FB63 A A C A FB64 A A C C FB65 A A C A FB66 A A C C FB67 A A C AFB68 A A C C FB69 A A C C FB70 A A C A FB71 A A C A FB72 A A C C

We claim:
 1. A process comprising reacting thiobiuret 2-2 with an alkyliodide to produce substituted product (3-1b)

wherein (A) Ar¹ is selected from (1) phenyl, pyridazinyl, pyridyl,pyrimidinyl, or (2) substituted phenyl, substituted pyridazinyl,substituted pyridyl, or substituted pyrimidinyl, wherein saidsubstituted phenyl, substituted pyridazinyl, substituted pyridyl, andsubstituted pyrimidinyl, have one or more substituents independentlyselected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, substituted phenyl andsubstituted phenoxy wherein such substituted phenyl and substitutedphenoxy have one or more substituents independently selected from H, F,Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y), C(═O)(C₁-C₆alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl),C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆alkyl), phenyl, and phenoxy; (B) Het is a 5- or 6-membered, saturated orunsaturated, heterocyclic ring, containing one or more heteroatomsindependently selected from nitrogen, sulfur, or oxygen, and where Ar¹and Ar² are not ortho to each other (but may be meta or para, such as,for a five-membered ring they are 1,3 and for a 6-membered ring they areeither 1,3 or 1,4) and where said heterocyclic ring may also besubstituted with one or more substituents independently selected from H,F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, substituted phenyl andsubstituted phenoxy wherein such substituted phenyl and substitutedphenoxy have one or more substituents independently selected from H, F,Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆haloalkyl), C(═O)H, C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y),C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), phenyl, and phenoxy;(C) Ar² is selected from (1) phenyl, pyridazinyl, pyridyl, pyrimidinyl,or (2) substituted phenyl, substituted pyridazinyl, substituted pyridyl,or substituted pyrimidinyl, wherein said substituted phenyl, substitutedpyridazinyl, substituted pyridyl, and substituted pyrimidinyl, have oneor more substituents independently selected from H, F, Cl, Br, I, CN,NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl),S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl),C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy,substituted phenyl and substituted phenoxy wherein such substitutedphenyl and substituted phenoxy have one or more substituentsindependently selected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR^(x)R^(y),(C₁-C₆ alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆alkyl), phenyl, and phenoxy; (D) R² is an alkyl; (E) R³ is selected fromphenyl, C₁-C₆ alkylphenyl, C₁-C₆ alkyl-O-phenyl, C₂-C₆ alkenyl-O-phenyl,(Het-1), C₁-C₆ alkyl(Het-1), or C₁-C₆ alkyl-O-(Het-1), wherein eachalkyl, alkenyl, phenyl, and (Het-1) are optionally substituted with oneor more substituents independently selected from F, Cl, Br, I, CN, NO₂,NR^(x)R^(y), C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆haloalkyl), C(═O)H, C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y),C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), O(C₁-C₆alkyl), S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl,phenoxy, and (Het-1); (F) R^(x) and R^(y) are independently selectedfrom H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl),S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl),C(═O)H, C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), and phenyl, wherein each alkyl, cycloalkyl,cycloalkoxy, alkoxy, alkenyl, alkynyl, and phenyl, are optionallysubstituted with one or more substituents independently selected from F,Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)OH, C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, halophenyl,phenoxy, and (Het-1), or R^(x) and R^(y) together can optionally form a5- to 7-membered saturated or unsaturated cyclic group which may containone or more heteroatoms selected from nitrogen, sulfur, and oxygen, andwhere said cyclic group may be substituted with F, Cl, Br, I, CN, oxo,thioxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl,S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl),OSO₂(C₁-C₆ haloalkyl), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, substitutedphenyl, phenoxy, and (Het-1); (G) L is linker selected from (1) asaturated or unsaturated, substituted or unsubstituted, linear(C₁-C₄)hydrocarbyl linker, or (2) a saturated or unsaturated,substituted or unsubstituted, cyclic (C₃-C₈)hydrocarbyl group linker,wherein said substituted linear (C₁-C₄)hydrocarbyl linker andsubstituted cyclic (C₃-C₈)hydrocarbyl linker has one or moresubstituents independently selected from R⁸, R⁹, R¹⁰, R¹¹, and R¹²,wherein each R⁸, R⁹, R¹⁰, R¹¹, and R¹², is selected from F, Cl, Br, I,CN, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, C₃-C₆halocycloalkyl, or phenyl; and (H) n is each individually 0, 1, or 2;and (I) (Het-1) is a 5- or 6-membered, saturated or unsaturated,heterocyclic ring, containing one or more heteroatoms independentlyselected from nitrogen, sulfur or oxygen, wherein said heterocyclic ringmay also be substituted with one or more substituents independentlyselected from H, F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)NR^(x)R^(y), (C₁-C₆alkyl)NR^(x)R^(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, substituted phenyl andsubstituted phenoxy, wherein such substituted phenyl and substitutedphenoxy have one or more substituents independently selected from H, F,Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆haloalkyl), C(═O)H, C(═O)NR^(x)R^(y), (C₁-C₆ alkyl)NR^(x)R^(y),C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), phenyl, and phenoxy.